Methods and compositions useful in treating cancer and reducing Wnt mediated effects in a cell

ABSTRACT

Provided herein are novel compounds, pharmaceutical compositions for use, inter alia, in methods of reducing Wnt-mediated effects and treating cancer.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/826,291, filed Nov. 29, 2017, which is a continuation of U.S.application Ser. No. 15/210,793, filed Jul. 14, 2016, which is acontinuation of U.S. application Ser. No. 14/529,796, filed Oct. 31,2014, which is a continuation of U.S. application Ser. No. 13/254,427,filed Oct. 3, 2011, which is a 371 of international application numberPCT/US2010/025984, filed Mar. 2, 2010, which claims the benefit of U.S.Provisional Application Ser. No. 61/156,741, filed Mar. 2, 2009, all ofwhich are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

The Wnt pathway is an evolutionarily conserved growth pathway inmulticellular organisms that regulates animal development and playscritical roles in human disease. Signaling through the Wnt pathway isregulated by secreted Wnt proteins, which act as morphogens tomediate 1) cell fate determination and differentiation required forestablishing the body plan, neural patterning, and organogenesis, 2)cell motility and polarity, 3) cell proliferation and apoptosis, and 4)stem cell maintenance.

In Wnt signaling, the transcriptional coactivator, beta-catenin, isconstitutively degraded in the absence of a Wnt signal thereby allowinga cell to maintain low cytoplasmic levels of beta-catenin and keepingthe Wnt pathway in the “off” position. Degradation of beta-cateninrequires its recruitment into a complex consisting primarily of Glycogensynthase kinase (Gsk3), Casein Kinase 1 (CK1), Protein phosphatase 2A(PP2A), Axin, and the tumor suppressor adenomatous polyposis coli (APC).Within this complex, beta-catenin is phosphorylated by CK1, which primesit for further phosphorylation by Gsk3. Phosphorylated beta-catenin isrecognized by the SCF (Skip 1, Cullen, F-box) ubiquitin ligase complex,of which the specificity F-box determinant is beta-TRCP, and targetedfor polyubiquitination and subsequent degradation by the proteasome. TheWnt pathway is turned “on” upon binding of Wnt ligands to the Frizzledfamily of receptors and the coreceptor family members LDLreceptor-related protein 5 or 6 (LRP5/6), which results in translocationof the beta-catenin destruction complex to the membrane throughinteraction of Axin with LRP5/6. The interaction between Axin and LRP5/6is promoted by the phosphorylation of LRP5/6 by CK1 and Gsk3, andAxin-LRP5/6 interaction results in inhibition of beta-cateninphosphorylation and degradation. Because beta-catenin is continuallysynthesized in cells, its cytoplasmic concentration increases, and itenters the nucleus and forms a complex with the TCF/LEF 1 family oftranscriptional factors (as well as the nuclear proteins BCL9 andPygopus) to regulate a Wnt-specific transcriptional program.

Our bodies are composed of numerous cell types specialized to performspecific functions. These specialized or differentiated cells arederived from a small group of stem and progenitor cells that have thecapacity to divide asymmetrically, allowing them to regeneratethemselves, and also giving rise to a daughter cell that candifferentiate into cell types characteristic of various organs in ourbodies. It is recognized that diseases like diabetes, Parkinson'sdisease, and heart disease are caused by death or dysfunction ofdifferentiated cells in tissues where stem cells are limiting. Thesediseases may be caused by loss of stem cell activity and/ormisregulation of critical signaling pathways in stem cells residing intissues such as the pancreas, brain, and heart. The Wnt pathway is a keyregulator of stem cell behavior and viability, and modulation of thispathway presents a method of treating diseases associated withdysfunctional stem cell activity. For example, activation of the Wntpathway has been associated with heart failure, and inhibition of Wntsignaling has been shown to improve recovery after a heart attack inanimal models. Thus, Wnt inhibitors could have broad applications inregenerative (stem cell) medicine for the treatment of major humandiseases such as heart disease.

Cancer has been shown to be stem cell related disease, resulting fromfailure of cells to respond to normal cues to stop proliferating. Wntsignaling is also a critical pathway that drives the uncontrolledproliferation of many solid tumors in cancer stem cells (CSCs). Thus,therapies that down-regulate the activity of Wnt signaling, afundamental pathway in CSCs, would be effective in the treatment ofcancer. Such inhibitors would result in a long-term therapeutic benefitbecause the cells capable of repopulating the tumor would be killed.Most notably, there is clear evidence that colorectal cancer arises frommutations in the stem cell compartment, and it has been demonstratedthat all major solid cancers in humans (e.g. melanoma, hepatocellularcarcinoma, and breast cancer) have abnormal Wnt signaling. Thus, Wntinhibitors may be useful in the treatment of most of the major solidcancers in humans.

BRIEF SUMMARY OF THE INVENTION

Provided herein, inter alia, are novel pharmaceutical compositions andmethods of reducing Wnt-mediated effects and treating cancer.

In one aspect, a compound is provided having the structure of Formula(IA) or (IB):

In Formulae (IA) and (IB), R¹ is substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R² ishydrogen, halogen, —CN, —CF₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R³ ishalogen, —CN, —CF₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁴ isindependently halogen, —CN, —CF₃, —NR^(4A)—C(O)R^(4B),—NR^(4A)—C(O)—OR^(4B), —C(O)NR^(4A)R^(4B), —NR^(4A)S(O)₂R^(4B),—S(O)₂N(R^(4A))(R^(4B)), —SR^(4A), —S(O)R^(4B), —S(O)₂R^(4B),—NR^(4A)R^(4B), —OR^(4A), C(O)R^(4B)D, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R^(4A) and R^(4B) are independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. The symbol w represents an integer from 0 to4. L¹ is -L²-N(R⁶¹)—C(O)—N(R⁶²)-L³-, -L²-N(R⁶¹)—C(O)-L³- or-L²C(O)—N(R⁶)-L³-. L² and L³ are independently a bond or substituted orunsubstituted alkylene. R⁶¹ and R⁶² are independently hydrogen, —CN,—CF₃, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In another aspect, a compound is provided having the structure ofFormula (XXIV):

In Formula (XXIV), R⁶⁶ and R are independently substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. R⁶⁸, R⁶⁹and R⁷⁰ are independently hydrogen, halogen, —CN, —CF₃,—NR^(68A)—C(O)R^(68B), —NR^(68A)—C(O)—OR^(68B), —C(O)NR^(68A)R^(68B),—NR^(68A)S(O)₂R^(68B), —S(O)₂N(R^(68A))(R^(68B)), —SR^(68A),—S(O)R^(68B), —S(O)₂R^(68B), —NR^(68A)R^(68B), —OR^(68A), —C(O)R^(68B),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R^(68A) and R^(68B) areindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. L⁶ is-L⁷-N(R⁷¹)—C(O)—N(R⁷²)-L⁸-, -L⁷-N(R⁶¹)—C(O)-L⁸- or -L⁷-C(O)—N(R⁷¹)-L⁸-.L⁷ and L⁸ are independently a bond or substituted or unsubstitutedalkylene. L⁴ and L⁵ are independently a bond or substituted orunsubstituted alkylene.

In another aspect, a method of reducing a Wnt-mediated effect on a cellis provided. The method includes contacting the cell with an effectiveamount of a compound provided herein (e.g. Formulae (IA) to (XXIIIA),(IB) to (XXIIIB) and (XXIV) and embodiments thereof), orpharmaceutically acceptable salt thereof.

In another aspect, a method of treating cancer in a subject in needthereof is provided. The method includes administering to the subject aneffective amount of a compound provided herein (e.g. Formulae (IA) to(XXIIIA), (IB) to (XXIIIB) and (XXIV) and embodiments thereof), orpharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a pharmaceuticalcomposition including a pharmaceutically acceptable excipient and acompound provided herein (e.g. Formulae (IA) to (XXIIIA), (IB) to(XXIIIB) and (XXIV) and embodiments thereof).

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e. unbranched) or branched chain,or combination thereof, which may be fully saturated, mono- orpolyunsaturated and can include di- and multivalent radicals, having thenumber of carbon atoms designated (i.e. C₁-C₁₀ means one to tencarbons). Examples of saturated hydrocarbon radicals include, but arenot limited to, groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkyl, as exemplified, but not limited,by —CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will havefrom 1 to 24 carbon atoms, with those groups having 10 or fewer carbonatoms being preferred in the present invention. A “lower alkyl” or“lower alkylene” is a shorter chain alkyl or alkylene group, generallyhaving eight or fewer carbon atoms.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of atleast one carbon atoms and at least one heteroatom selected from thegroup consisting of O, N, P, Si and S, and wherein the nitrogen andsulfur atoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) O, N, P, S and Si may beplaced at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, O—CH₃, —O—CH₂—CH₃, and —CN. Up to two heteroatoms maybe consecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.Similarly, the term “heteroalkylene” by itself or as part of anothersubstituent means a divalent radical derived from heteroalkyl, asexemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini (e.g., alkylenoxy,alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Stillfurther, for alkylene and heteroalkylene linking groups, no orientationof the linking group is implied by the direction in which the formula ofthe linking group is written. For example, the formula —C(O)₂R′—represents both —C(O)₂R′— and —R′C(O)₂—. As described above, heteroalkylgroups, as used herein, include those groups that are attached to theremainder of the molecule through a heteroatom, such as —C(O)R′,—C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where “heteroalkyl” isrecited, followed by recitations of specific heteroalkyl groups, such as—NR′R or the like, it will be understood that the terms heteroalkyl and—NR′R″ are not redundant or mutually exclusive. Rather, the specificheteroalkyl groups are recited to add clarity. Thus, the term“heteroalkyl” should not be interpreted herein as excluding specificheteroalkyl groups, such as —NR′R or the like.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively, which can be asingle ring or multiple rings (preferably from 1 to 3 rings) which arefused together or linked covalently. Additionally, for heterocycloalkyl,a heteroatom can occupy the position at which the heterocycle isattached to the remainder of the molecule. Examples of cycloalkylinclude, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and“heterocycloalkylene” refer to a divalent radical derived fromcycloalkyl and heterocycloalkyl, respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent which can be a single ring or multiplerings (preferably from 1 to 3 rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a carbon or heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl,1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl,4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. “Arylene” and “heteroarylene”refers to a divalent radical derived from a aryl and heteroaryl,respectively.

The term “oxo” as used herein means an oxygen that is double bonded to acarbon atom.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”), unless otherwise noted, are meant to include bothsubstituted and unsubstituted forms of the indicated radical. Where asubstituent is R-substituted (e.g. an R¹⁶-substituted alkyl), thesubstituent may be substituted with one or more R groups as allowed bychemical valency rules where each R group is optionally different (e.g.an R¹⁶-substituted alkyl may include multiple R¹⁶ groups wherein eachR¹⁶ group is optionally different). Certain examples of substituents foreach type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylenyl, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″, R″′ and R″″ eachpreferably independently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g.,aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl,alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R″′ and R″″ groupswhen more than one of these groups is present. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: halogen, —OR′, —NR′R″, —SR′, -halogen,—SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R″″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl,in a number ranging from zero to the total number of open valences onthe aromatic ring system; and where R′, R″, R″′ and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl. When a compound of the invention includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R″′ and R″″ groups when more than one of these groupsis present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′— or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R′)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″ and R″′ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

As used herein, the term “heteroatom” or “ring heteroatom” is meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, Oxo, halogen, unsubstituted        alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl,        unsubstituted heterocycloalkyl, unsubstituted aryl,        unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo (where allowed according to valency rules), —OH,            —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, unsubstituted alkyl,            unsubstituted heteroalkyl, unsubstituted cycloalkyl,            unsubstituted heterocycloalkyl, unsubstituted aryl,            unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            and heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo (where allowed according to valency rules, —OH,                —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, unsubstituted                alkyl, unsubstituted heteroalkyl, unsubstituted                cycloalkyl, unsubstituted heterocycloalkyl,                unsubstituted aryl, unsubstituted heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, or heteroaryl, substituted with at least one                substituent selected from oxo (where allowed according                to valency rules, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂,                halogen, unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, and unsubstituted                heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₄-C₈cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 4 to 8 membered heterocycloalkyl.

A “lower substituent” or “lower substituent group,” as used herein meansa group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl isa substituted or unsubstituted C₁-C₅ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₅-C₇ cycloalkyl, and each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7membered heterocycloalkyl.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., “Pharmaceutical Salts”, Journal ofPharmaceutical Science, 1977, 66, 1-19). Certain specific compounds ofthe present invention contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts.

Thus, the compounds of the present invention may exist as salts withpharmaceutically acceptable acids. The present invention includes suchsalts. Examples of such salts include hydrochlorides, hydrobromides,sulfates, methanesulfonates, nitrates, maleates, acetates, citrates,fumarates, tartrates (eg (+)-tartrates, (−)-tartrates or mixturesthereof including racemic mixtures, succinates, benzoates and salts withamino acids such as glutamic acid. These salts may be prepared bymethods known to those skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,tautomers, geometric isomers and individual isomers are encompassedwithin the scope of the present invention. The compounds of the presentinvention do not include those which are known in the art to be toounstable to synthesize and/or isolate.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

The symbol

denotes a point of attachment of a moiety to the remainder of acompound.

The phrase “effective amount” refers to an amount sufficient to attainthe desired result. The phrase “therapeutically effective amount” meansan amount sufficient to produce the desired therapeutic result.Generally the therapeutic result is an objective or subjectiveimprovement of a disease or condition, achieved by inducing or enhancinga physiological process, blocking or inhibiting a physiological process,or in general terms performing a biological function that helps in orcontributes to the elimination or abatement of the disease or condition.

The terms “treat,” “treating” or “treatment,” and other grammaticalequivalents as used herein, include alleviating, abating or amelioratinga disease or condition symptoms, preventing additional symptoms,ameliorating or preventing the underlying metabolic causes of symptoms,inhibiting the disease or condition, e.g., arresting the development ofthe disease or condition, relieving the disease or condition, causingregression of the disease or condition, relieving a condition caused bythe disease or condition, or stopping the symptoms of the disease orcondition, and prophylaxis. The terms further include achieving atherapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying disorderbeing treated. Also, a therapeutic benefit is achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the patient, notwithstanding that the patient may still beafflicted with the underlying disorder. For prophylactic benefit, thecompositions may be administered to a patient at risk of developing aparticular disease, or to a patient reporting one or more of thephysiological symptoms of a disease, even though a diagnosis of thisdisease may not have been made.

As used herein, the term “cancer” refers to all types of cancer,neoplasm, or malignant tumors found in mammals, including leukemia,carcinomas and sarcomas. Exemplary cancers include cancer of the brain,breast, cervix, colon, head & neck, liver, kidney, lung, non-small celllung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus andMedulloblastoma. Additional examples include, Hodgkin's Disease,Non-Hodgkin's Lymphoma, multiple mycloma, neuroblastoma, ovarian cancer,rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,primary brain tumors, cancer, malignant pancreatic insulanoma, malignantcarcinoid, urinary bladder cancer, premalignant skin lesions, testicularcancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer,genitourinary tract cancer, malignant hypercalcemia, endometrial cancer,adrenal cortical cancer, neoplasms of the endocrine and exocrinepancreas, and prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). The P₃₈₈ leukemia model is widely accepted as beingpredictive of in vivo anti-leukemic activity. It is believed that acompound that tests positive in the P₃₈₈ assay will generally exhibitsome level of anti-leukemic activity in vivo regardless of the type ofleukemia being treated. Accordingly, the present invention includes amethod of treating leukemia, and, preferably, a method of treating acutenonlymphocytic leukemia, chronic lymphocytic leukemia, acutegranulocytic leukemia, chronic granulocytic leukemia, acutepromyelocytic leukemia, adult T-cell leukemia, alcukemic leukemia, aleukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovineleukemia, chronic myelocytic leukemia, leukemia cutis, embryonalleukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia,hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia,stem cell leukemia, acute monocytic leukemia, leukopenic leukemia,lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia,lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia,mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia,monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloidgranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasmacell leukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, and undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas which can be treated with a combination ofantineoplastic thiol-binding mitochondrial oxidant and an anticanceragent include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas which can betreated with a combination of antineoplastic thiol-binding mitochondrialoxidant and an anticancer agent include, for example, acral-lentiginousmelanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman'smelanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma,lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungalmelanoma, and superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas which can be treated with acombination of antineoplastic thiol-binding mitochondrial oxidant and ananticancer agent include, for example, acinar carcinoma, acinouscarcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinomaadenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolarcell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloidcarcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma,bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma,cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma,comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma encuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cellcarcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma,encephaloid carcinoma, epiermoid carcinoma, carcinoma epithelialeadenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum,gclatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma,carcinoma gigantocellulare, glandular carcinoma, granulosa cellcarcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellularcarcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroidcarcinoma, infantile embryonal carcinoma, carcinoma in situ,intraepidermal carcinoma, intraepithelial carcinoma, Krompecher'scarcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticularcarcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelialcarcinoma, carcinoma medullare, medullary carcinoma, melanoticcarcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum,carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum,mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oatcell carcinoma, carcinoma ossificans, osteoid carcinoma, papillarycarcinoma, periportal carcinoma, preinvasive carcinoma, prickle cellcarcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reservecell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma,scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma,carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidalcell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamouscarcinoma, squamous cell carcinoma, string carcinoma, carcinomatelangiectaticum, carcinoma telangiectodes, transitional cell carcinoma,carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, andcarcinoma villosum.

II. Compounds

In one aspect, compounds are provided for use in the methods disclosedherein and for incorporation into certain pharmaceutical compositionsdescribed herein.

In some embodiments, the compound has the structure of formula (IA) or(IB):

In Formulae (IA) and (IB), R¹ is substituted or unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substituted orunsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

In some embodiments, where R′ is a substituted substituent, R′ issubstituted with R¹⁶. For example, in some embodiments, R¹ isR¹⁶-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R¹⁶-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R¹⁶-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R¹⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R¹⁶-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR¹⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R¹⁶ is oxo (where permitted according to valency rules), halogen, —CN,—CF₃, —NR^(16A)—C(O)R^(16B), —NR^(16A)—C(O)—OR^(16B),—C(O)NR^(16A)R^(16B), —NR^(16A)S(O)₂R^(16B), —S(O)₂N(R^(16A))(R^(16B)),—SR^(16A), —S(O)R^(16B), —S(O)₂R^(16B), —NR^(16A)R^(16B), —OR^(16A),—C(O)R^(16B), R¹⁷-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R¹⁷-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R¹⁷-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R¹⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R¹⁷-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR¹⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(16A) and R^(16B) are independently hydrogen, R¹⁷-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R¹⁷-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R¹⁷-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R¹⁷-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R¹⁷-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R¹⁷-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R¹⁷ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(17A)—C(O)R^(17B), —NR^(17A)—C(O)—OR^(17B),—C(O)NR^(17A)R^(17B), —NR^(17A)S(O)₂R^(17B), —S(O)₂N(R^(17A))(R^(17B)),—SR^(17A), —S(O)R^(17B), —S(O)₂R^(17B), —NR^(17A)R^(17B), —OR^(17A),—C(O)R^(17B), R¹⁸-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R¹⁸-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R¹⁸-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R¹⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R¹⁸-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR¹⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(17A) and R^(17B) are independently hydrogen, R¹⁸-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R′⁸-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R¹⁸-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R¹⁸-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R¹⁸-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R¹⁸-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R¹⁸ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(1A)—C(O)R^(18B), —NR^(18A)—C(O)—OR^(18B),—C(O)NR^(18A)R^(18B), —NR^(18A)S(O)₂R^(18B), —S(O)₂N(R^(18A))(R^(18B)),—SR^(18A), —S(O)R^(18B), —S(O)₂R^(18B), —NR^(18A)R^(18B), —OR^(18A),—C(O)R^(18B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(18A) and R^(18B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R² is hydrogen, halogen, —CN, —CF₃, substituted or unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substituted orunsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures). In some embodiments, R² is methyl, ethyl,propyl, tertiary butyl, methylene cyclopropyl (—CH₂-cyclopropyl),methoxy, ethoxy, propoxy, butoxy or —CF₃.

In some embodiments, where R² is a substituted substituent, R² issubstituted with R¹⁹. For example, in some embodiments, R¹ isR¹⁹-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R¹⁹-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R¹⁹-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R¹⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R¹⁹-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR¹⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R¹⁹ is oxo (where permitted according to valency rules), halogen, —CN,—CF₃, —NR^(19A)—C(O)R^(19B), —NR^(19A)—C(O)—OR^(19B),—C(O)NR^(19A)R^(19B), —NR^(19A)S(O)₂R^(19B), —S(O)₂N(R^(19A))(R^(19B)),—SR^(19A), —S(O)R^(19B), —S(O)₂R^(19B), —NR^(19A)R^(19B), —OR^(19A),C(O)R^(19B), R²⁰-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R²⁰-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R²⁰-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R²⁰-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R²⁰-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR²⁰-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(19A) and R^(19B) are independently hydrogen, R²⁰-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R²⁰-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R²⁰-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R²⁰-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R²⁰-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R²⁰-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R²⁰ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(20A)—C(O)R^(20B), —NR^(2A)—C(O)—OR^(20B),—C(O)NR^(20A)R^(20B), —NR^(20A)S(O)₂R^(20B), —S(O)₂N(R^(20A))(R^(20B)),—SR^(20A), —S(O)R^(20B), —S(O)₂R^(20B), —NR^(20A)R^(20B), —OR^(20A),—C(O)R^(20B), R²¹-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R²¹-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R²¹-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R²¹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R²¹-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR²¹-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(20A) and R^(20B) are independently hydrogen, R²¹-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R²¹-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R²¹-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R²¹-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R²¹-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R²¹-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R²¹ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(21A)—C(O)R^(21B), —NR^(21A)—C(O)—OR^(21B),—C(O)NR^(21A)R^(21B), —NR^(21A)S(O)₂R^(21B), —S(O)₂N(R^(21A))(R^(21B)),—SR^(21A), —S(O)R^(21B), —S(O)₂R^(21B), —NR^(21A)R^(21B), —OR^(21A),—C(O)R^(21B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(21A) and R^(21B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R³ is halogen, —CN, —CF₃, substituted or unsubstituted alkyl (e.g.substituted or unsubstituted C₁ to C₂₀ alkyl), substituted orunsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

In some embodiments, where R³ is a substituted substituent, R³ issubstituted with R²². For example, in some embodiments, R³ isR²²-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R²²-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R²²-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R²²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R²²-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR²²-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R²² is oxo (where permitted according to valency rules), halogen, —CN,—CF₃, —NR^(22A)—C(O)R^(22B), —NR^(22A)—C(O)—OR^(22B),—C(O)NR^(22A)R^(22B), —NR^(22A)S(O)₂R^(22B), —S(O)₂N(R^(22A))(R^(22B)),—SR^(22A), —S(O)R^(22B), —S(O)₂R^(22B), —NR^(22A)R^(22B), —OR^(22A),—C(O)R^(22B), —R²³-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R²³-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R²³-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R²³-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R²³-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR²³-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(22A) and R^(22B) are independently hydrogen, R²³-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R²³-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R²³-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R²³-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R²³-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R²³-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R²³ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(23A)—C(O)R^(23B), —NR^(23A)—C(O)—OR^(23B),—C(O)NR^(23A)R^(23B), —NR^(23A)S(O)₂R^(23B), —S(O)₂N(R^(23A))(R^(23B)),—SR^(23A), —S(O)R^(23B), —S(O)₂R^(23B), —NR^(23A)R^(23B), —OR^(23A),—C(O)R^(23B), R²⁴-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R²⁴⁻substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R²⁴-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R²⁴-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R²⁴-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR²⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(23A) and R^(23B) are independently hydrogen, R²⁴-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R²⁴-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R²⁴-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R²⁴⁻substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R²⁴-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R²⁴-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R²⁴ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(24A)—C(O)R^(24B), —NR^(24A)—C(O)—OR^(24B),—C(O)NR^(24A)R^(24B), —NR^(24A)S(O)₂R^(24B), —S(O)₂N(R^(24A))(R^(24B)),—SR^(24A), —S(O)R^(24B), —S(O)₂R^(24B), —NR^(24A)R^(24B), —OR^(24A),—C(O)R^(24B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(24A) and R^(24B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R⁴ is independently halogen, —CN, —CF₃, —NR^(4A)—C(O)R^(4B),—NR^(4A)—C(O)—OR^(4B), —C(O)NR^(4A)R^(4B), —NR^(4A)S(O)₂R^(4B),—S(O)₂N(R^(4A))(R^(4B)), —SR^(4A), —S(O)R^(4B), —S(O)₂R^(4B),—NR^(4A)R^(4B), —OR^(4A), —C(O)R^(4B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(4A) and R^(4B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R⁴, R^(4A) and R^(4B) are substitutedsubstituents, R⁴, R^(4A) and R⁴ are independently substituted with R²⁵.For example, in some embodiments, R⁴, R^(4A) and R⁴ are independentlyR²⁵-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R²⁵-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R²⁵-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R²⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R²⁵-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR²⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R²⁵ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(25A)—C(O)R^(25B), —NR^(25A)—C(O)—OR^(25B),—C(O)NR^(25A)R^(25B), —NR^(25A)S(O)₂R^(25B), —S(O)₂N(R^(25A))(R^(25B)),—SR^(25A), —S(O)R^(25B), —S(O)₂R^(25B), —NR^(25A)R^(25B), —OR^(25A),—C(O)R^(25B), R²⁶-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R²⁶-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R²⁶-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R²⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R²⁶-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR²⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(25A) and R^(25B) are independently hydrogen, R²⁶-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R²⁶-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R²⁶-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R²⁶-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R²⁶-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R²⁶-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R²⁶ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(26A)—C(O)R^(26B), —NR^(26A)—C(O)—OR^(26B),—C(O)NR^(26A)R^(26B), —NR^(26A)S(O)₂R^(26B), —S(O)₂N(R^(26A))(R^(26B)),—SR²⁶, S(O)R^(26B), —S(O)₂R^(26B), NR^(26A)R²⁶, OR²⁶, C(O)R^(26B),R²⁷-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R²⁷-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R²⁷-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R²⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R²⁷-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR²⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(26A) and R^(26B) are independently hydrogen, R²⁷-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R²⁷-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R²⁷-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R²⁷-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R²⁷-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R²⁷-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R²⁷ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(27A)—C(O)R^(27B), —NR^(27A)—C(O)—OR^(27B),—C(O)NR^(27A)R^(27B), —NR^(27A)S(O)₂R^(27B), —S(O)₂N(R^(27A))(R^(27B)),—SR^(27A), —S(O)R^(27B), —S(O)₂R^(27B), —NR^(27A)R^(27B), —OR^(27A),—C(O)R^(27B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(27A) and R^(27B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

The symbol w is an integer from 0 to 4. In some embodiments, w is 0. Inother embodiments, w is 1.

L is -L²-N(R⁶¹)—C(O)—N(R⁶²)-L³-, -L²-N(R⁶¹)—C(O)-L³- or-L²-C(O)—N(R⁶)-L³-. L² and L³ are independently a bond or substituted orunsubstituted alkylene (e.g. substituted or unsubstituted C₁ to C₂₀alkylene). In some embodiments, L² and L³ are independently a bond orsubstituted or unsubstituted C₁ to C₁₀ alkylene. In other embodiments,L² and L³ are independently a bond or substituted or unsubstituted C₁ toC₅ alkylene. L² and L³ may also independently be a bond or unsubstitutedmethylene. In some embodiments, L² and L³ are a bond.

In some embodiments, where L² and L³ are substituted, L² and L³ areindependently substituted with R⁶⁶. For example, in some embodiments, L²and L³ are independently R⁶⁶-substituted or unsubstituted alkylene (e.g.substituted or unsubstituted C₁ to C₂₀ alkylene). R⁶⁶ is independentlyoxo (where permitted according to valency rules), halogen, —CN, —CF₃,—NR^(66A)—C(O)R^(66B), —NR^(66A)—C(O)—OR^(66B), —C(O)NR^(66A)R^(66B),—NR^(66A)S(O)₂R^(66B), —S(O)₂N(R^(66A))(R^(66B)), —SR^(66A),—S(O)R^(66B), —S(O)₂R^(66B), —NR^(66A)R^(66B)OR^(66A), C(O)R^(66B),unsubstituted alkyl (e.g. substituted or unsubstituted C to C₂₀ alkyl),unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄cycloalkyl including fused ring structures), unsubstitutedheterocycloalkyl (e.g. 3 to 14 membered heterocycloalkyl including fusedring structures), unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures). R^(66A) andR^(66B) are independently hydrogen, unsubstituted alkyl (e.g.substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstituted heteroalkyl(e.g. substituted or unsubstituted 2 to 20 membered heteroalkyl),unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), unsubstituted heterocycloalkyl (e.g. 3 to 14 memberedheterocycloalkyl including fused ring structures), unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orunsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R⁶¹ and R⁶² are independently hydrogen, —CN, —CF₃, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R⁶¹ and R⁶² are a substituted substituent,R⁶¹ and R⁶² are independently substituted with R⁶³. For example, in someembodiments, R⁶¹ and R⁶³ are independently R⁶³-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁶³-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁶³-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁶³-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁶³-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁶³-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁶³ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(63A)—C(O)R^(63B), —NR^(63A)—C(O)—OR^(63B),—C(O)NR^(63A)R^(63B), —NR⁶³S(O)₂R^(63B), —S(O)₂N(R^(63A))(R^(63B)),—SR^(63A), —S(O)R^(63B), —S(O)₂R^(63B), —NR^(63A)R^(63B), OR^(63A),—C(O)R^(63B), R⁶⁴-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁶⁴-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁶⁴-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁶⁴-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁶⁴-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁶⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(63A) and R^(63B) are independently hydrogen, R⁶⁴-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁶⁴-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁶⁴-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁶⁴-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁶⁴-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁶⁴-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁶⁴ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(64A)—C(O)R^(64B), —NR^(64A)—C(O)—OR^(64B),—C(O)NR^(64A)R^(64B), —NR^(64A)S(O)₂R^(64B), —S(O)₂N(R^(64A))(R^(64B)),—SR^(64A), —S(O)R^(64B), —S(O)₂R^(64B), —NR^(64A)R^(64B), —OR^(64A),—C(O)R^(64B), R⁶⁵ substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁶⁵-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁶⁵-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁶⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁶⁵-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁶⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(64A) and R^(64B) are independently hydrogen, R⁶⁵-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁶⁵-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁶⁵-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁶⁵-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁶⁵-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁶⁵-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁶⁵ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(65A)—C(O)R⁶⁵, —NR^(65A)—C(O)—OR^(5B),—C(O)NR^(65A)R^(65B), —NR^(65A)S(O)₂R⁶⁵, —S(O)₂N(R^(65A))(R^(65B)),—SR^(65A), —S(O)R^(65B), —S(O)₂R^(65B), —NR^(65A)R^(65B), —OR^(65A),—C(O)R^(65B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(65A) and R^(65B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R⁶¹ and R⁶² are independently hydrogen, halogen,—CN, —CF₃, —OH, —NH₂, R⁶³-substituted or unsubstituted C₁ to C₅ alkyl,or R⁶³-substituted or unsubstituted 2 to 6 membered heteroalkyl, whereinR⁶³ is oxo, halogen, —CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl,unsubstituted 2 to 6 membered heteroalkyl, or unsubstituted C₃ to C₆cycloalkyl (e.g. cyclopropyl). In some embodiments, R⁶¹ and R⁶² areindependently hydrogen, methyl, ethyl, propyl, tertiary butyl, orcyclopropyl methylene (—CH₂-cyclopropyl). In some embodiments, R⁶¹ andR⁶² are hydrogen.

In some embodiments, L¹ is —NH—C(O)—. Where L¹ is —NH—C(O)— as usedherein (as opposed to a —C(O)—NH—), the orientation of the L¹ groups isas provided below:

Thus, where L¹ is —NH—C(O)— for a formula provided herein, it isintended that the amide carbon is attached to the phenyl group and amidenitrogen is attached to the R¹ group.

In some embodiments, R¹ is a substituted (e.g. R¹⁶-substituted) orunsubstituted heteroaryl (e.g. a 5 to 14 membered heteroaryl includingfused ring heteroaryls) or a substituted (e.g. R¹⁶-substituted) orunsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures). In some embodiments, R¹ is a substituted (e.g.R¹⁶-substituted) or unsubstituted heteroaryl (e.g. a 5 to 14 memberedheteroaryl including fused ring heteroaryls) or a substituted (e.g.R¹⁶-substituted) or unsubstituted phenyl. R¹ may also be substituted(e.g. R¹⁶-substituted) or unsubstituted pyridinyl, substituted (e.g.R¹⁶-substituted) or unsubstituted thiazolyl, substituted (e.g.R¹⁶-substituted) or unsubstituted benzothiazolyl, substituted (e.g.R¹⁶-substituted) or unsubstituted oxazolyl, substituted (e.g.R¹⁶-substituted) or unsubstituted phenyl, substituted (e.g.R¹⁶-substituted) or unsubstituted 4,5-dihydro-1H-benzoindazolyl orsubstituted (e.g. R¹⁶-substituted) or unsubstituted pyrazolyl. Incertain embodiments, R¹ is substituted (e.g. R¹⁶-substituted) orunsubstituted phenyl. In certain embodiments, R¹ is substituted (e.g.R¹⁶-substituted) or unsubstituted thiazolyl. In certain embodiments, R¹is substituted (e.g. R¹⁶-substituted) or unsubstituted benzothizoolyl.In certain embodiments, R¹ is substituted (e.g. R¹⁶-substituted) orunsubstituted 4,5-dihydro-1H-benzoindazolyl. In certain embodiments, R¹is substituted (e.g. R¹⁶-substituted) or unsubstituted pyrazolyl. Incertain embodiments, R¹ is substituted (e.g. R¹⁶-substituted) orunsubstituted pyridinyl.

In some embodiments, where R¹ is a R¹⁶-substituted or unsubstitutedheteroaryl (e.g. a 5 to 14 membered heteroaryl including fused ringheteroaryls) or a R¹⁶-substituted or unsubstituted aryl (e.g. a C₆ toC₁₄ aryl including fused ring structures), R¹⁶ is an R¹⁷-substituted orunsubstituted heteroaryl (e.g. a 5 to 14 membered heteroaryl includingfused ring heteroaryls) or R¹⁷-substituted or unsubstituted aryl (e.g. aC₆ to C₁₄ aryl including fused ring structures). In some embodiments,where R¹ is R¹⁶-substituted or unsubstituted thiazolyl, R¹⁶ is anR¹⁷-substituted or unsubstituted (e.g. a 5 to 14 membered heteroarylincluding fused ring heteroaryls) or R¹⁷-substituted or unsubstitutedaryl (e.g. a C₆ to C₁₄ aryl including fused ring structures). In someembodiments, where R¹ is R¹⁶-substituted or unsubstituted thiazolyl, R¹⁶is an R¹⁷-substituted or unsubstituted pyridinyl or R¹⁷-substituted orunsubstituted phenyl. R¹⁷ may be halogen, —CN, —CF₃, —OH, —NH₂,R¹⁸-substituted or unsubstituted C₁ to C₅ alkyl, R¹⁸-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R¹⁸ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl.

In some embodiments, where R′ is R¹⁶-substituted or unsubstitutedthiazolyl, R¹⁶ is an R¹⁷-substituted or unsubstituted pyridinyl. In someembodiments, where R¹ is R¹⁶-substituted or unsubstituted thiazolyl, R¹⁶is an R¹⁷-substituted or unsubstituted pyridinyl. R¹⁷ may be halogen,—CN, —CF₃, —OH, —NH₂, R′⁸-substituted or unsubstituted C₁ to C₅ alkyl,or R⁸-substituted or unsubstituted 2 to 6 membered heteroalkyl, whereinR′⁸ is oxo, halogen, —CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl,unsubstituted 2 to 6 membered heteroalkyl. In some embodiments, R¹ isR¹⁶-substituted or unsubstituted thiazolyl and R¹⁶ is unsubstitutedpyridinyl.

In some embodiments, R² is hydrogen or unsubstituted alkyl (e.g. C₁ toC₁₀ alkyl). In some embodiments, R² is hydrogen. In some embodiments, R²is unsubstituted C₁ to C₅ alkyl. In some embodiments, R² is methyl. Insome embodiments, R² is methyl, ethyl, propyl, tertiary butyl, methylenecyclopropyl (—CH₂-cyclopropyl), methoxy, ethoxy, propoxy, butoxy or—CF₃. These embodiments are applicable to all appropriate formulae asset forth herein.

R³ may be substituted (e.g. R²²-substituted) or unsubstituted phenyl. Insome embodiments, R²² is joined together with R² to form a substituted(e.g. R⁶-substituted as defined below) or unsubstituted heteroaryl orsubstituted (e.g. R⁶-substituted) or unsubstituted heterocycloalkyl. Inother embodiments, R² and R³ are joined together to form a substituted(e.g. R⁶-substituted) or unsubstituted heteroaryl. R² and R³ may bejoined together to form a substituted (e.g. R⁶-substituted) orunsubstituted indolin-1-yl or a substituted (e.g. R⁶-substituted) orunsubstituted tetrahydroquinolinyl. In some embodiments, R⁶ is halogen,—CN, —CF₃, —OH, —NH₂, R³¹-substituted or unsubstituted C₁ to C₅ alkyl,or R³¹-substituted or unsubstituted 2 to 6 membered heteroalkyl, whereinR³¹ is oxo, halogen, —CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl,unsubstituted 2 to 6 membered heteroalkyl.

In some embodiments, where R³ is R²²-substituted or unsubstitutedphenyl, R²² is halogen, —CN, —CF₃, —OH, —NH₂, R²³-substituted orunsubstituted C₁ to C₅ alkyl, or R²³-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²³ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl.

R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.

In some embodiments, the compound has the structure of formula (IIA) or(IIB):

In formulae (IIA) and (IIB), L¹, R¹, R², R⁴ and w are as defined above.In some embodiments, R¹ is substituted (e.g. R¹⁶-substituted) orunsubstituted aryl (e.g. C₆ to C₁₄ aryl including fused ring aryls) orsubstituted (e.g. R¹⁶-substituted) or unsubstituted heteroaryl (e.g. 5to 14 membered heteroaryl including fused rings structures). In someembodiments, w is 0. In other embodiments, w is 1. In some embodiments,L¹ is —NH—C(O)— as illustrated in Formula (IC1) or (IC2). R⁴ may behalogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted or unsubstituted C₁ to C₅alkyl, or R²⁵-substituted or unsubstituted 2 to 6 membered heteroalkyl,wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂, unsubstituted C₁ toC₅ alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In someembodiments, R⁴ is not F. In some embodiments, R⁴ is not halogen. Insome embodiments, R⁴ is —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is —CF₃, —OH, —NH₂, unsubstituted C₁to C₅ alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In someembodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.

R² is as defined above, and may be joined together with R⁵ to form asubstituted or unsubstituted (e.g. R⁶-substituted) heterocycloalkyl(e.g. 3 to 14 membered heterocycloalkyl including fused ring structures)or substituted (e.g. R¹⁶-substituted) or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures). In someembodiments, R² and R⁵ are not joined together to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. In some embodiments, R² is hydrogen or unsubstituted alkyl(e.g. C₁ to C₁₀ alkyl). In some embodiments, R² is hydrogen. In someembodiments, R² is unsubstituted C₁ to C₅ alkyl. In some embodiments, R²is methyl. In some embodiments, R² is methyl, ethyl, propyl, tertiarybutyl, methylene cyclopropyl (—CH₂-cyclopropyl), methoxy, ethoxy,propoxy, butoxy or —CF₃.

R⁵ is hydrogen, halogen, —CN, —CF₃, —NR^(5A)—C(O)R^(5B),—NR^(5A)—C(O)—OR^(5B), —C(O)NR^(5A)R^(5B), —NR^(5A)S(O)₂R^(5B),—S(O)₂N(R^(5A))(R^(5B)), —SR^(5A), —S(O)R^(5B), —S(O)₂R^(5B),—NR^(5A)R^(5B), —OR^(5A), —C(O)R^(5B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(5A), R^(5B) are independently hydrogen, substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

In some embodiments, where R⁵, R^(5A) and R^(5B) are substitutedsubstituents, R⁵, R^(5A) and R⁵ are independently substituted with R²⁸.For example, in some embodiments, R⁵, R^(5A) and R⁵ are independentlyR²⁸-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R²⁸-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R²⁸-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R²⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R²⁸-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR²⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R²⁸ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(28A)—C(O)R^(28B), —NR^(28A)—C(O)—OR^(28B),—C(O)NR^(28A)R^(28B), —NR^(28A)S(O)₂R^(21B), —S(O)₂N(R^(28A))(R^(28B)),—SR^(28A), —S(O)R^(28B), —S(O)₂R^(28B), —NR^(28A)R^(28B), —OR^(28A),—C(O)R^(28B), R²⁹ substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R²⁹-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R²⁹-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R²⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R²⁹-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR²⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(28A) and R^(28B) are independently hydrogen, R²⁹-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R²⁹-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R²⁹-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R²⁹-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R²⁹-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R²⁹-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R²⁹ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(29A)—C(O)R^(29B), —NR^(29A)—C(O)—OR^(29B),—C(O)NR^(29A)R^(29B), —NR^(29A)S(O)₂R^(29B), —S(O)₂N(R^(29A))(R^(29B)),—SR^(29A), —S(O)R^(29B), —S(O)₂R^(29B), —NR^(29A)R^(29B), OR^(29A),—C(O)R^(29B), R³⁰-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R³⁰-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R³⁰-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R³⁰-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R³⁰-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR³⁰-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(29A) and R^(29B) are independently hydrogen, R³⁰-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R³⁰-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R³⁰-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R¹⁰-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R³⁰-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R³⁰-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R³⁰ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(30A)—C(O)R^(30B), —NR^(30A)—C(O)—OR^(30B),—C(O)NR^(30A)R^(30B), —NR^(30A)S(O)₂R^(30B), —S(O)₂N(R^(30A))(R^(30B)),SR^(30A), S(O)R^(30B), —S(O)₂R^(30B), —NR^(30A)R^(30B), OR^(30A),C(O)R^(30B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(30A) and R^(30B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R⁵ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R²⁸-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁸-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁸ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁵ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁵ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁵ is methoxy.

R⁶ is independently halogen, —CN, —CF₃, —NR^(6A)—C(O)R^(6B),—NR^(6A)—C(O)—OR^(6B), —C(O)NR^(6A)R^(6B), —NR^(6A)S(O)₂R^(6B),—S(O)₂N(R^(6A))(R^(6B)), —SR^(6A), —S(O)R^(6B), —S(O)₂R^(6B),—NR^(6A)R^(6B), —OR^(6A), —C(O)R^(6B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(6A) and R^(6B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R⁶, R^(6A) and R^(6B) are substitutedsubstituents, R⁶, R^(6A) and R⁶ are independently substituted with R³¹.For example, in some embodiments, R⁶, R^(6A) and R⁶ are independentlyR³¹-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R³¹-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R³¹-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R³¹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R³¹-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR³¹-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R³¹ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(31A)—C(O)R^(31B), —NR^(31A)—C(O)—OR^(31B),—C(O)NR^(31A)R^(31B), —NR^(31A)S(O)₂R^(31B), —S(O)₂N(R^(31A))(R^(31B)),—SR^(31A), —S(O)R^(31B), —S(O)₂R^(31B), —NR^(31A)R^(31B), —OR^(31A),—C(O)R^(31B), R³²-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R³²-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R³²-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R³²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R³²-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR³²-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(31A) and R^(31B) are independently hydrogen, R³²-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R³²-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R³²-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R³²-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R³²-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R³²-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R³² is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(32A)—C(O)R^(32B), —NR^(32A)—C(O)—OR^(32B),—C(O)NR^(32A)R^(32B), —NR^(32A)S(O)₂R^(32B), —S(O)₂N(R^(32A))(R^(32B)),—SR^(32A), —S(O)R^(32B), —S(O)₂R^(32B), —NR^(32A)R^(32B), —OR^(32A),—C(O)R^(32B), R³³-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R³³-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R³³-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R³³-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R³³-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR³³-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(32A) and R^(32D) are independently hydrogen, R³³-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R³³-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R³³-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R³³-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R³³-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R³³-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R³³ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(33A)—C(O)R^(33B), —NR^(33A)—C(O)—OR^(33B),—C(O)NR^(33A)R^(33B), —NR^(33A)S(O)₂R^(33B), —S(O)₂N(R^(33A))(R^(33B)),—SR^(33A), —S(O)R^(33B), —S(O)₂R^(33B), —NR^(33A)R^(33B), —OR^(33A),—C(O)R^(33B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(33A) and R^(33B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, the compound has the formula:

In Formulae (IIIA) and (IIIB), R¹, L¹, R⁴, R⁶, w and z are as definedabove. In some embodiments, w is 0. In other embodiments, w is 1. Insome embodiments, L¹ is —NH—C(O)— as illustrated in Formula (IC1) or(IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.

In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, the compound has the formula:

In Formulae (IVA) and (IVB), R¹, L¹, R⁴, R⁶, w and z are as definedabove. In some embodiments, w is 0. In other embodiments, w is 1. Insome embodiments, L¹ is —NH—C(O)— as illustrated in Formula (IC1) or(IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, the compound has the formula:

In Formulae (VA) and (VB), R², R⁴, R⁵, R⁶, L¹, w and z are as definedabove. In some embodiments, w is 0. In other embodiments, w is 1. Insome embodiments, L¹ is —NH—C(O)— as illustrated in Formula (IC1) or(IC2). As set forth above in Formulae (IIA) and (IIB), R² may be joinedtogether with R⁵ to form a substituted or unsubstituted (e.g.R⁶⁻substituted) heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures) or substituted (e.g. R¹⁶-substituted)or unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures). In some embodiments of Formulae (VA) and (VB),R² and R⁵ are not joined together to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl. In someembodiments, R² is hydrogen or unsubstituted alkyl (e.g. C₁ to C₁₀alkyl). In some embodiments, R² is hydrogen. In some embodiments, R² isunsubstituted C₁ to C₅ alkyl. In some embodiments, R² is methyl. In someembodiments, R² is methyl, ethyl, propyl, tertiary butyl, methylenecyclopropyl (—CH₂-cyclopropyl), methoxy, ethoxy, propoxy, butoxy or—CF₃.

R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

R⁷ is hydrogen, halogen, —CN, —CF₃, —NR^(7A)—C(O)R^(7B),—NR^(7A)—C(O)—OR^(7B), —C(O)NR^(7A)R^(7B), —NR^(7A)S(O)₂R^(7B),—S(O)₂N(R^(7A))(R^(7B)), —SR^(7A), —S(O)R^(7B), —S(O)₂R^(7B),—NR^(7A)R^(7B), —OR^(7A), —C(O)R^(7B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(7A) and R^(7B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R⁷, R^(7A) and R^(7B) are substitutedsubstituents, R⁷, R^(7A) and R⁷ are independently substituted with R³⁴.For example, in some embodiments, R⁷, R^(7A) and R⁷ are independentlyR³⁴-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R³⁴-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R³⁴-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R³⁴-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R³⁴-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR³⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R³⁴ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(34A)—C(O)R^(34B), —NR^(34A)—C(O)—OR^(34B),—C(O)NR^(34A)R^(34B), —NR^(34A)S(O)₂R^(34B), —S(O)₂N(R^(34A))(R^(34B)),—SR^(34A), —S(O)R^(34B), —S(O)₂R^(34B), —NR^(34A)R^(34B), —OR^(34A),—C(O)R^(34B), R³⁵-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R³⁵-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R³⁵-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R³⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R³⁵-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR³⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(34A) and R^(34B) are independently hydrogen, R³⁵-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R³⁵-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R³⁵-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R³⁵-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R³⁵-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R³⁵-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R³⁵ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(35A)—C(O)R^(35B), —NR^(35A)—C(O)—OR^(35B),—C(O)NR^(35A)R^(35B), —NR^(35A)S(O)₂R^(35B), —S(O)₂N(R^(35A))(R^(35B)),—SR^(35A), —S(O)R^(35B), —S(O)₂R^(35B), —NR^(35A)R^(35B), —OR^(35A),—C(O)R^(35B), R³⁶-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R³⁶-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R³⁶-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R³⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R³⁶-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR³⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(35A) and R^(35B) are independently hydrogen, R³⁶-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R³⁶-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R³⁶-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R³⁶-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R³⁶-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R³⁶-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R³⁶ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(36A)—C(O)R³⁶, —NR^(36A)—C(O)—OR^(36B),—C(O)NR^(36A)R^(36B), —NR^(36A)S(O)₂R³⁶, —S(O)₂N(R^(36A))(R^(36B)),—SR^(36A), —S(O)R^(36B), —S(O)₂R^(36B), NR^(36A)R^(36B), —OR^(36A),—C(O)R^(36B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(36A) and R^(36B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R⁸ is hydrogen, halogen, —CN, —CF₃, —NR^(8A)—C(O)R^(8B),—NR^(8A)—C(O)—OR^(8B), —C(O)NR^(8A)R^(8B), —NR^(8A)S(O)₂R^(8B),—S(O)₂N(R^(8A))(R^(8B)), —SR^(8A), —S(O)R^(8B), —S(O)₂R^(8B),—NR^(8A)R^(8B), —OR^(8A), —C(O)R^(8B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R⁷ and R⁸ are optionally joined together to form a substituted (e.g.R¹⁵-substituted as defined below) or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted (e.g.R¹⁵-substituted as defined below) or unsubstituted heterocycloalkyl(e.g. 3 to 14 membered heterocycloalkyl including fused ringstructures), substituted (e.g. R¹⁵-substituted as defined below) orunsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted (e.g. R¹⁵-substituted as defined below) orunsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(8A) and R^(8B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R⁸, R^(8A) and R^(8B) are substitutedsubstituents, R⁸, R^(8A) and R⁸ are independently substituted with R³⁷.For example, in some embodiments, R⁸, R^(8A) and R⁸ are independentlyR³⁷-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R³⁷-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R³⁷-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R³⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R³⁷-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR³⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R³⁷ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(37A)—C(O)R^(37B), —NR^(37A)—C(O)—OR^(37B),—C(O)NR^(37A)R^(37B), —NR^(37A)S(O)₂R^(37B), —S(O)₂N(R^(37A))(R^(37B)),—SR^(37A), S(O)R^(37B), —S(O)₂R^(37B), NR^(37A)R^(37B), OR^(37A),C(O)R^(37B), R⁸-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R³⁸-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R³⁸-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R³⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R³⁸-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR³⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(37A) and R^(37B) are independently hydrogen, R³⁸-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R³⁸-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R³⁸-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R³⁸-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R³⁸-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R³⁸-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R³⁸ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(38A)—C(O)R^(38B), —NR^(38A)—C(O)—OR^(38B),—C(O)NR^(38A)R^(38B), —NR^(38A)S(O)₂R^(38B), —S(O)₂N(R^(38A))(R^(38B)),—SR^(38A), —S(O)R^(38B), —S(O)₂R^(38B), —NR^(38A)R^(38B), —OR^(38A),—C(O)R^(38B), R³⁹-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R³⁹-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R³⁹-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R³⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R³⁹-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR³⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R³SA and R^(38B) are independently hydrogen, R³⁹-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R³⁹-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R³⁹-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R³⁹-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R³⁹-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R³⁹-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R³⁹ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(39A)—C(O)R^(39B), —NR^(39A)—C(O)—OR^(39B),—C(O)NR^(39A)R^(39B), —NR^(39A)S(O)₂R^(39B), —S(O)₂N(R^(39A))(R^(39B)),—SR^(39A), —S(O)R^(39B), —S(O)₂R^(39B), —NR^(39A)R^(39B), —OR^(39A),—C(O)R^(39B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(39A) and R^(39B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R⁵ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R²⁸-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁸-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁸ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁵ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁵ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁵ is methoxy.

In some embodiments, R⁸ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R³⁷-substituted or unsubstituted C₁ to C₅ alkyl, or R³⁷-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³⁷ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁸ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R⁸ is hydrogen, —F, methyl or methoxy. In some embodiments,R⁸ is hydrogen.

In some embodiments, the compound has the formula:

In Formulae (VIA) and (VIB), R⁴, R⁶, R⁷, R⁸, L¹, w and z are as definedabove. In some embodiments, w is 0. In other embodiments, w is 1. Insome embodiments, L¹ is —NH—C(O)— as illustrated in Formula (IC1) or(IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R⁸ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R³⁷-substituted or unsubstituted C₁ to C₅ alkyl, or R³⁷-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³⁷ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁸ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R⁸ is hydrogen, —F, methyl or methoxy. In some embodiments,R⁸ is hydrogen.

In some embodiments, the compound has the formula:

In Formulae (VIIA) and (VIIB), R⁴, R⁶, R⁷, R⁸, L¹, w and z are asdefined above. In some embodiments, w is 0. In other embodiments, wis 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substitutedor unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2to 6 membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R⁸ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R³⁷-substituted or unsubstituted C₁ to C₅ alkyl, or R³⁷-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³⁷ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁸ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R⁸ is hydrogen, —F, methyl or methoxy. In some embodiments,R⁸ is hydrogen.

In some embodiments, the compound has the formula:

In Formulae (VIIIA) and (VIIIB), R², R⁴, R⁵, R⁶, R⁸, L¹, w and z are asdefined above. In some embodiments, w is 0. In other embodiments, wis 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). X¹ and X² are independently carbon or nitrogen. A personhaving ordinary skill in the art will immediately recognize that whencarbon, X¹ and/or X² may optionally be attached to substituent R⁹.

As set forth above in Formulae (IIA), (IIB), (VA) and (VB) above, R² maybe joined together with R⁵ to form a substituted or unsubstituted (e.g.R⁶-substituted) heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures) or substituted (e.g. R¹⁶-substituted)or unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures). In some embodiments of Formulae (VIIIA) and(VIIIB), R² and R⁵ are not joined together to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. In some embodiments, R² is hydrogen or unsubstituted alkyl(e.g. C₁ to C₁₀ alkyl). In some embodiments, R² is hydrogen. In someembodiments, R² is unsubstituted C₁ to C₅ alkyl. In some embodiments, R²is methyl. In some embodiments, R² is methyl, ethyl, propyl, tertiarybutyl, methylene cyclopropyl (—CH₂-cyclopropyl), methoxy, ethoxy,propoxy, butoxy or —CF₃.

R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R⁸ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R³⁷⁻substituted or unsubstituted C₁ to C₅ alkyl, or R³⁷-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³⁷ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁸ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R⁸ is hydrogen, —F, methyl or methoxy. In some embodiments,R⁸ is hydrogen.

R⁹ is independently halogen, —CN, —CF₃, —NR^(9A)—C(O)R^(9B),—NR^(9A)—C(O)—OR^(9B), —C(O)NR^(9A)R^(9B), —NR^(9A)S(O)₂R^(9B),—S(O)₂N(R^(9A))(R^(9B)), —SR^(9A), —S(O)R^(9B), —S(O)₂R^(9B),—NR^(9A)R^(9B), —OR^(9A), —C(O)R^(9B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(9A) and R^(9B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R⁹, R^(9A) and R^(OB) are substitutedsubstituents, R⁹, R^(9A) and R⁹ are independently substituted with R⁴⁰.For example, in some embodiments, R⁹, R^(9A) and R⁹ are independentlyR⁴⁰-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R⁴⁰-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁴⁰-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁴⁰-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁴⁰-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁴⁰-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R⁴⁰ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(40A)—C(O)R^(40B), —NR^(40A)—C(O)—OR^(40B),—C(O)NR^(40A)R^(40B), —NR^(40A)S(O)₂R^(40B), —S(O)₂N(R^(40A))(R^(40B)),—SR^(40A), —S(O)R^(40B), —S(O)₂R^(40B), —NR^(40A)R^(40B), —OR^(40A),—C(O)R^(40B), R⁴¹-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁴¹-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁴¹-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁴¹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁴¹-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁴¹-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(40A) and R^(40B) are independently hydrogen, R⁴¹-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁴¹-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁴¹-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁴¹-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁴¹-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁴¹-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁴¹ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(41A)—C(O)R^(41B), —NR^(41A)—C(O)—OR⁴,—C(O)NR^(41A)R⁴¹, —NR^(41A)S(O)₂R^(41B), —S(O)₂N(R^(41A))(R^(41B)),—SR^(41A), —S(O)R^(41B), —S(O)₂R^(41B), —NR^(41A)R^(41B), —OR^(41A),—C(O)R^(41B), R⁴² substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁴²-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁴²-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁴²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁴²-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁴²-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(41A) and R^(41B) are independently hydrogen, R⁴²-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁴²-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁴²-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁴²-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁴²-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁴²-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁴² is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(42A)—C(O)R^(42B), —NR^(42A)—C(O)—OR^(42B),—C(O)NR^(42A)R^(42B), —NR^(42A)S(O)₂R^(42B), —S(O)₂N(R^(42A))(R^(42B)),—SR^(42A), —S(O)R^(42B), —S(O)₂R^(42B), —NR^(42A)R^(42B), —OR^(42A),—C(O)R^(42B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(42A) and R^(42B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R⁵ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R²⁸-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁸-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁸ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁵ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁵ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁵ is methoxy.

In some embodiments, R⁹ is halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁰-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁰-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁰ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁹ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R⁹ is —F,methyl or methoxy. The symbol u is an integer from 0 to 5. In someembodiments, u is 0. In other embodiments, u is 1. In some embodiments,X¹ and X² are carbon. In other embodiments, X¹ is carbon and X² isnitrogen.

In some embodiments, the compound has the formula:

In Formulae (I×A) and (I×B), R⁴, R⁶, R⁸, R⁹, L¹, u, w and z are asdefined above. In some embodiments, w is 0. In other embodiments, wis 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substitutedor unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2to 6 membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R⁸ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R³⁷-substituted or unsubstituted C₁ to C₅ alkyl, or R³⁷-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³⁷ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁸ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R⁸ is hydrogen, —F, methyl or methoxy. In some embodiments,R⁸ is hydrogen.

In some embodiments, R⁹ is halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁰-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁰-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁰ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁹ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R⁹ is —F,methyl or methoxy. The symbol u is an integer from 0 to 5. In someembodiments, u is 0. In other embodiments, u is 1. In some embodiments,X¹ and X² are carbon. In other embodiments, X¹ is carbon and X² isnitrogen.

In some embodiments, the compound has the formula:

In Formulae (XA) and (XB), R⁴, R⁶, R⁸, R⁹, L¹, u, w and z are as definedabove. In some embodiments, w is 0. In other embodiments, w is 1. Insome embodiments, L¹ is —NH—C(O)— as illustrated in Formula (IC1) or(IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R^(3′) is oxo,halogen, —CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl,unsubstituted 2 to 6 membered heteroalkyl. In some embodiments, R⁶ ismethoxy, ethoxy, propoxy, Cl, F or CF₃. In some embodiments, R⁶ ismethoxy, ethoxy, or propoxy. In some embodiments, R⁶ is methoxy. Thesymbol z is an integer from 0 to 4. In some embodiments, z is 0. Inother embodiments z is one. Where z is one, R⁶ may be attached to thephenyl ring para to the sulfonamide moiety. In other embodiments where zis one, R⁶ is attached to the phenyl ring meta to the sulfonamidemoiety.

In some embodiments, R⁸ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R³⁷-substituted or unsubstituted C₁ to C₅ alkyl, or R³⁷-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³⁷ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁵ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R⁵ is hydrogen, —F, methyl or methoxy. In some embodiments,R⁸ is hydrogen.

In some embodiments, R⁹ is halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁰-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁰-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁰ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁹ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R⁹ is —F,methyl or methoxy. The symbol u is an integer from 0 to 5. In someembodiments, u is 0. In other embodiments, u is 1. In some embodiments,X¹ and X² are carbon. In other embodiments, X¹ is carbon and X² isnitrogen.

In some embodiments, the compound has the formula:

In Formulae (XIA) and (XIB), R², R⁴, R⁵, R⁶, L¹, z and w are as definedabove. In some embodiments, w is 0. In other embodiments, w is 1. Insome embodiments, L¹ is —NH—C(O)— as illustrated in Formula (IC1) or(IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

As set forth above in Formulae (IIA), (IIB), (VA), (VB), (VIIIA) and(VIIIB) above, R² may be joined together with R⁵ to form a substitutedor unsubstituted (e.g. R⁶-substituted) heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures) orsubstituted (e.g. R¹⁶-substituted) or unsubstituted heteroaryl (e.g. 5to 14 membered heteroaryl including fused rings structures). In someembodiments of Formulae (XIA) and (XIB), R² and R⁵ are not joinedtogether to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl. In some embodiments, R² ishydrogen or unsubstituted alkyl (e.g. C₁ to C₁₀ alkyl). In someembodiments, R² is hydrogen. In some embodiments, R² is unsubstituted C₁to C₅ alkyl. In some embodiments, R² is methyl. In some embodiments, R²is methyl, ethyl, propyl, tertiary butyl, methylene cyclopropyl(—CH₂-cyclopropyl), methoxy, ethoxy, propoxy, butoxy or —CF₃.

R¹⁰ is hydrogen, halogen, —CN, —CF₃, —NR^(10A)—C(O)R^(10B),—NR^(10A)—C(O)—OR^(10B), —C(O)NR^(10A)R^(10B), —NR^(10A)S(O)₂R^(10B),—S(O)₂N(R^(10A))(R^(10B)), —SR¹⁰, —S(O)R^(10B), —S(O)₂R^(10B),—NR^(10A)R^(10B), —OR^(10A), —C(O)R^(10B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(10A) and R^(10B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R¹⁰, R^(10A) and R^(10B) are substitutedsubstituents, R¹⁰, R^(10A) and R¹⁰ are independently substituted withR⁴³. For example, in some embodiments, R¹⁰, R^(10A) and R^(10B) areindependently R⁴³-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁴³-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁴³-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁴³-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁴³-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁴³-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R⁴³ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(43A)—C(O)R^(43B), —NR^(43A)—C(O)—OR^(43B),—C(O)NR^(43A)R^(43B), —NR^(43A)S(O)₂R^(43B), —S(O)₂N(R^(43A))(R^(43B)),—SR^(43A), —S(O)R^(43B), —S(O)₂R^(43B), NR^(43A)R^(43B), —OR^(43A),—C(O)R^(43B), R⁴⁴-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁴⁴-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁴⁴-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁴⁴-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁴⁴-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁴⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(43A) and R^(43B) are independently hydrogen, R⁴⁴-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁴⁴-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁴⁴-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁴⁴-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁴⁴-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁴⁴-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁴⁴ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(44A)—C(O)R^(44B), —NR^(44A)—C(O)—OR^(44B),—C(O)NR^(44A)R^(44B), —NR^(44A)S(O)₂R^(44B), —S(O)₂N(R^(44A))(R^(44B)),—SR^(44A), —S(O)R^(44B), —S(O)₂R^(44B), —NR^(44A)R^(44B), —OR^(44A),—C(O)R^(44B), R⁴⁵-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁴⁵-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁴⁵-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁴⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁴⁵-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁴⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(44A) and R^(44B) are independently hydrogen, R⁴⁵-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁴⁵-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁴⁵-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁴⁵-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁴⁵-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁴⁵-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁴⁵ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(45A)—C(O)R^(45B), —NR^(45A)—C(O)—OR^(45B),—C(O)NR^(45A)R^(45B), —NR^(45A)S(O)₂R^(45B), —S(O)₂N(R^(45A))(R^(45B)),SR⁴⁵, S(O)R^(45B), —S(O)₂R^(45B), —NR^(45A)R^(45B), OR^(45A),C(O)R^(45B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(45A) and R^(45B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R⁵ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R²⁸-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁸-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁸ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁵ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁵ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁵ is methoxy.

In some embodiments, R¹⁰ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴³-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴³-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴³ is Oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹⁰ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹⁰ is hydrogen, —F, methyl or methoxy. In someembodiments, R¹⁰ is hydrogen.

R¹¹ is hydrogen, halogen, —CN, —CF₃, —NR^(11A)—C(O)R^(11B),—NR^(11A)—C(O)—OR^(11B), —C(O)NR^(11A)R^(11B), —NR^(11A)S(O)₂R^(11B),—S(O)₂N(R^(11A))(R^(11B)), —SR^(11A), —S(O)R^(11B), —S(O)₂R^(11B),—NR^(11A)R^(11B), —OR^(11A), —C(O)R^(11B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(11A) and R^(11B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R¹¹, R^(11A) and R^(11B) are substitutedsubstituents, R¹¹, R^(11A) and R¹¹ are independently substituted withR⁴⁶. For example, in some embodiments, R¹¹, R^(11A) and R^(11B) areindependently R⁴⁶-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁴⁶-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁴⁶-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁴⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁴⁶-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁴⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R⁴⁶ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(46A)—C(O)R^(46B), —NR^(46A)—C(O)—OR^(46B),—C(O)NR^(46A)R^(46B), —NR^(46A)S(O)₂R^(46B), —S(O)₂N(R^(46A))(R^(46B)),—SR^(46A), —S(O)R^(46B), —S(O)₂R^(46B), NR^(46A)R^(46B), —OR^(46A),—C(O)R⁴⁶, R⁴⁷-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R⁴⁷-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁴⁷-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁴⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁴⁷-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁴⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(46A) and R^(46B) are independently hydrogen, R⁴⁷-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁴⁷-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁴⁷-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁴⁷-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁴⁷-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁴⁷-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁴⁷ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(47A)—C(O)R^(47B), —NR^(47A)—C(O)—OR^(47B),—C(O)NR^(47A)R^(47B), —NR^(47A)S(O)₂R^(47B), —S(O)₂N(R^(47A))(R^(47B)),—SR^(47A), —S(O)R^(47B), —S(O)₂R^(47B), —NR^(47A)R^(47B), —OR^(47A),—C(O)R^(47B), R⁴⁸ substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁴⁸-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁴⁸-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁴⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁴⁸-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁴⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(47A) and R^(47B) are independently hydrogen, R⁴⁸-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁴⁸-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁴⁸-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁴⁸-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁴⁸-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁴⁸-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁴⁸ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(48A)—C(O)R^(48B), —NR^(48A)—C(O)—OR^(48B),—C(O)NR^(48A)R^(48B), —NR^(48A)S(O)₂R^(48B), —S(O)₂N(R^(48A))(R^(48B)),—SR^(48A), —S(O)R^(48B), —S(O)₂R^(48B), —NR^(48A)R^(48B), —OR^(48A),—C(O)R^(48B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(48A) and R^(48B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R¹¹ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁶-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁶-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁶ is Oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹¹ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹¹ is hydrogen, —F, methyl or methoxy. In someembodiments, R¹¹ is hydrogen.

R¹² is hydrogen, halogen, —CN, —CF₃, —NR^(12A)—C(O)R^(12B),—NR^(12A)—C(O)—OR^(12B), —C(O)NR^(12A)R^(12B), —NR^(12A)S(O)₂R^(12B),—S(O)₂N(R^(12A))(R^(12B)), —SR^(12A), —S(O)R^(12B), —S(O)₂R^(12B),—NR^(12A)R^(12B), —OR^(12A), —C(O)R^(12B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(12A) and R^(12B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R¹², R^(12A) and R^(12B) are substitutedsubstituents, R¹², R^(12A) and R′² are independently substituted withR⁴⁹. For example, in some embodiments, R¹², R^(12A) and R^(12B) areindependently R⁴⁹-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁴⁹-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁴⁹-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁴⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁴⁹-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁴⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R⁴⁹ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(49A)—C(O)R^(49B), —NR^(49A)—C(O)—OR^(49B),—C(O)NR^(49A)R^(49B), —NR^(49A)S(O)₂R^(49B), —S(O)₂N(R^(49A))(R^(49B)),—SR^(49A), S(O)R^(49B), —S(O)₂R^(49B), —NR^(49A)R^(49B), —OR^(49A),—C(O)R^(49B), R⁰-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R⁵⁰-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁵⁰-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁵⁰-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁵⁰-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁵⁰-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(49A) and R^(49B) are independently hydrogen, R⁵⁰-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁵⁰-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁵⁰-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁵⁰-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁵⁰-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁵⁰-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁵⁰ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(50A)—C(O)R^(50B), NR^(50A)—C(O)—OR^(50B),—C(O)NR^(50A)R^(50B), —NR^(50A)S(O)₂R^(50B), —S(O)₂N(R^(50A))(R^(50B)),—SR^(50A), —S(O)R^(50B), —S(O)₂R^(50B), —NR^(50A)R^(50B), —OR^(50A),—C(O)R^(50B), R⁵¹-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁵¹-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁵¹-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁵¹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁵¹-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁵¹-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(50A) and R⁵⁰ are independently hydrogen, R⁵¹-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁵¹-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁵¹-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁵¹-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁵¹-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁵¹-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁵¹ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(51A)—C(O)R^(51B), —NR^(51A)—C(O)—OR^(51B),—C(O)NR^(51A)R^(51B), —NR^(51A)S(O)₂R^(51B), —S(O)₂N(R^(51A))(R^(51B)),—SR^(51A), —S(O)R^(51B), —S(O)₂R^(51B), —NR^(51A)R^(51B), —OR^(51A),—C(O)R^(51B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(51A) and R^(51B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R¹² is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁹-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R′² is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹² is hydrogen, —F, methyl or methoxy. In someembodiments, R¹² is hydrogen.

In some embodiment, the compound has the formula:

In Formulae (XIIA) and (XIIB), R⁴, R⁶, R¹⁰, R¹¹, R¹², L¹, w and z are asdefined above. In some embodiments, w is 0. In other embodiments, wis 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substitutedor unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2to 6 membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R¹⁰ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴³-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴³-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴³ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹⁰ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹⁰ is hydrogen, —F, methyl or methoxy. In someembodiments, R¹⁰ is hydrogen.

In some embodiments, R¹¹ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁶-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁶-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁶ is Oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹¹ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹¹ is hydrogen, —F, methyl or methoxy. In someembodiments, R¹¹ is hydrogen.

In some embodiments, R¹² is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁹-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹² is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹² is hydrogen, —F, methyl or methoxy. In someembodiments, R¹¹ is hydrogen.

In some embodiment, the compound has the formula:

In Formulae (XIIIA) and (XIIIB), R⁴, R⁶, R¹⁰, R¹¹, R¹², L¹, w and z areas defined above. In some embodiments, w is 0. In other embodiments, wis 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substitutedor unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2to 6 membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R¹⁰ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴³-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴³-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴³ is Oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹⁰ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹⁰ is hydrogen, —F, methyl or methoxy. In someembodiments, R¹⁰ is hydrogen.

In some embodiments, R¹¹ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁶-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁶-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁶ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹¹ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹¹ is hydrogen, —F, methyl or methoxy. In someembodiments, R¹¹ is hydrogen.

In some embodiments, R¹² is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁹-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹² is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹² is hydrogen, —F, methyl or methoxy. In someembodiments, R¹¹ is hydrogen.

In some embodiments, the compound has the formula:

In Formulae (XIVA) and (XIVB), R², R⁴, R⁵, R⁶, L¹, w and z are asdefined above. The symbol m is an integer from 0 to 5. In someembodiments, w is 0. In other embodiments, w is 1. In some embodiments,L¹ is —NH—C(O)— as illustrated in Formula (IC1) or (IC2). R⁴ may behalogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted or unsubstituted C₁ to C₅alkyl, or R²⁵-substituted or unsubstituted 2 to 6 membered heteroalkyl,wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂, unsubstituted C₁ toC₅ alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In someembodiments, R⁴ is not F. In some embodiments, R⁴ is not halogen. Insome embodiments, R⁴ is —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is —CF₃, —OH, —NH₂, unsubstituted C₁to C₅ alkyl, or unsubstituted 2 to 6 membered heteroalkyl. In someembodiments, R⁴ is methyl, methoxy, —CF₃, or —OH. In some embodiments,R⁶ is halogen, —CN, —CF₃, —OH, —NH₂, R³¹-substituted or unsubstituted C₁to C₅ alkyl, or R³¹-substituted or unsubstituted 2 to 6 memberedheteroalkyl, wherein R³¹ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6 membered heteroalkyl.In some embodiments, R⁶ is methoxy, ethoxy, propoxy, Cl, F or CF₃. Insome embodiments, R⁶ is methoxy, ethoxy, or propoxy. In someembodiments, R⁶ is methoxy. The symbol z is an integer from 0 to 4. Insome embodiments, z is 0. In other embodiments z is one. Where z is one,R⁶ may be attached to the phenyl ring para to the sulfonamide moiety. Inother embodiments where z is one, R⁶ is attached to the phenyl ring metato the sulfonamide moiety.

As set forth above in Formulae (IIA), (IIB), (VA), (VB), (VIIIA),(VIIIB), (XIA) and (XIB) above, R² may be joined together with R⁵ toform a substituted or unsubstituted (e.g. R⁶-substituted)heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkyl including fusedring structures) or substituted (e.g. R¹⁶-substituted) or unsubstitutedheteroaryl (e.g. 5 to 14 membered heteroaryl including fused ringsstructures). In some embodiments of Formulae (XIVA) and (XIVB), R² andR⁵ are not joined together to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl. In someembodiments, R² is hydrogen or unsubstituted alkyl (e.g. C₁ to C₁₀alkyl). In some embodiments, R² is hydrogen. In some embodiments, R² isunsubstituted C₁ to C₅ alkyl. In some embodiments, R² is methyl. In someembodiments, R² is methyl, ethyl, propyl, tertiary butyl, methylenecyclopropyl (—CH₂-cyclopropyl), methoxy, ethoxy, propoxy, butoxy or—CF₃.

R¹³ is independently halogen, —CN, —CF₃, —NR^(13A)—C(O)R^(13B),—NR^(13A)—C(O)—OR^(13B), —C(O)NR^(13A)R^(13B), —NR^(13A)S(O)₂R^(13B),—S(O)₂N(R^(13A))(R^(13B)), —SR^(13A), —S(O)R^(13B), —S(O)₂R^(13B),—NR^(13A)R^(13B), —OR^(13A), —C(O)R^(13B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(13A) and R^(13B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R¹³, R^(13A) and R^(13B) are substitutedsubstituents, R¹³, R^(13A) and R¹³ are independently substituted withR⁵². For example, in some embodiments, R¹³, R^(13A) and R^(13B) areindependently R⁵²-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁵²-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁵²-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁵²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁵²-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁵²-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R⁵² is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(52A)—C(O)R^(52B), —NR^(52A)—C(O)—OR^(52B),—C(O)NR^(52A)R^(52B), —NR^(52A)S(O)₂R^(52B), —S(O)₂N(R^(52A))(R^(52B)),—SR^(52A), —S(O)R^(52B), —S(O)₂R^(52B), —NR^(52A)R^(52B), —OR^(52A),—C(O)R^(52B), R⁵³-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁵³-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁵³-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁵³-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁵³-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁵³-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(52A) and R^(52B) are independently hydrogen, R⁵³-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁵³-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁵³-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁵³-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁵³-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁵³-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁵³ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(53A)—C(O)R^(53B), —NR^(53A)—C(O)—OR^(53B),—C(O)NR^(53A)R^(53B), —NR^(53A)S(O)₂R^(53B), —S(O)₂N(R^(53A))(R^(53B)),SR⁵³, S(O)R^(53B), —S(O)₂R⁵³, NR^(53A)R^(53B), OR⁵³, C(O)R⁵³,R⁵⁴-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R⁵⁴-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁵⁴-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁵⁴-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁵⁴-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁵⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(53A) and R^(53B) are independently hydrogen, R⁵⁴-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁵⁴-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁵⁴-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁵⁴-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁵⁴-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁵⁴-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁵⁴ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(54A)—C(O)R^(54B), —NR^(54A)—C(O)—OR^(54B),—C(O)NR^(54A)R^(54B), —NR^(54A)S(O)₂R^(54B), —S(O)₂N(R^(54A))(R^(54B)),—SR^(54A), —S(O)R^(54B), —S(O)₂R^(54B), —NR^(54A)R^(54B), —OR^(54A),—C(O)R^(54B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(54A) and R^(54B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R⁵ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R²⁸-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁸-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁸ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁵ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁵ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁵ is methoxy.

In some embodiments, R¹³ is halogen, —CN, —CF₃, —OH, —NH₂,R⁵²-substituted or unsubstituted C₁ to C₅ alkyl, or R⁵²-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁵² is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹³ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R¹³ is-F,methyl or methoxy. In some embodiments, m is 0. In other embodiments, mis one.

In some embodiments, the compound has the formula:

In Formulae (XVA) and (XVB), R⁴, R⁶, R¹³, L¹, w, z and m are as definedabove. In some embodiments, w is 0. In other embodiments, w is 1. Insome embodiments, L¹ is —NH—C(O)— as illustrated in Formula (IC1) or(IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R¹³ is halogen, —CN, —CF₃, —OH, —NH₂,R⁵²-substituted or unsubstituted C₁ to C₅ alkyl, or R⁵²-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁵² is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹³ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R¹³ is-F,methyl or methoxy. In some embodiments, m is 0. In other embodiments, mis one.

In some embodiments, the compound has the formula:

In Formulae (XVIA) and (XVIB), R⁴, R⁶, R¹³, L¹, w, z and m are asdefined above. In some embodiments, w is 0. In other embodiments, wis 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substitutedor unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2to 6 membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R¹³ is halogen, —CN, —CF₃, —OH, —NH₂,R⁵²-substituted or unsubstituted C₁ to C₅ alkyl, or R⁵²-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁵² is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹³ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R¹³ is-F,methyl or methoxy. In some embodiments, m is 0. In other embodiments, mis one.

In some embodiments, the compound has the formula:

In Formulae (XVIIA) and (XVIIB), L¹, R², R⁴, R⁵, R⁶, R⁸, R⁹, z, w and uare as defined above. In some embodiments, w is 0. In other embodiments,w is 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substitutedor unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2to 6 membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.As set forth above in Formulae (IIA), (IIB), (VA), (VB), (VIIIA),(VIIIB), (XIA), (XIB), (XIVA) and (XIVB) above, R² may be joinedtogether with R⁵ to form a substituted or unsubstituted (e.g.R⁶-substituted) heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures) or substituted (e.g. R¹⁶-substituted)or unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures). In some embodiments of Formulae (XVIIA) or(XVIIB), R² and R⁵ are not joined together to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. In some embodiments, R² is hydrogen or unsubstituted alkyl(e.g. C₁ to C₁₀ alkyl). In some embodiments, R² is hydrogen. In someembodiments, R² is unsubstituted C₁ to C₅ alkyl. In some embodiments, R²is methyl. In some embodiments, R² is methyl, ethyl, propyl, tertiarybutyl, methylene cyclopropyl (—CH₂-cyclopropyl), methoxy, ethoxy,propoxy, butoxy or —CF₃. In some embodiments, R⁶ is halogen, —CN, —CF₃,—OH, —NH₂, R³¹-substituted or unsubstituted C₁ to C₅ alkyl, orR³¹-substituted or unsubstituted 2 to 6 membered heteroalkyl, whereinR³¹ is oxo, halogen, —CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl,unsubstituted 2 to 6 membered heteroalkyl. In some embodiments, R⁶ ismethoxy, ethoxy, propoxy, Cl, F or CF₃. In some embodiments, R⁶ ismethoxy, ethoxy, or propoxy. In some embodiments, R⁶ is methoxy. Thesymbol z is an integer from 0 to 4. In some embodiments, z is 0. Inother embodiments z is one. Where z is one, R⁶ may be attached to thephenyl ring para to the sulfonamide moiety. In other embodiments where zis one, R⁶ is attached to the phenyl ring meta to the sulfonamidemoiety.

In some embodiments, R⁵ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R²⁸-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁸-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁸ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁵ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁵ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁵ is methoxy.

In some embodiments, R⁸ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R³⁷-substituted or unsubstituted C₁ to C₅ alkyl, or R³⁷-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³⁷ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁸ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R⁸ is hydrogen, —F, methyl or methoxy. In some embodiments,R⁸ is hydrogen.

In some embodiments, R⁹ is halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁰-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁰-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁰ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁹ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R⁹ is —F,methyl or methoxy. The symbol u is an integer from 0 to 5. In someembodiments, u is 0. In other embodiments, u is 1. In some embodiments,X¹ and X² are carbon. In other embodiments, X¹ is carbon and X² isnitrogen.

In some embodiments, the compound has the formula:

In Formulae (XVIIIA) and (XVIIIB), L¹, R⁴, R⁸, R⁹, z, w and u are asdefined above. In some embodiments, w is 0. In other embodiments, wis 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substitutedor unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2to 6 membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R⁸ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R³⁷-substituted or unsubstituted C₁ to C₅ alkyl, or R³⁷-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³⁷ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁸ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R⁸ is hydrogen, —F, methyl or methoxy. In some embodiments,R⁵ is hydrogen.

In some embodiments, R⁹ is halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁰-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁰-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁰ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁹ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R⁹ is —F,methyl or methoxy. The symbol u is an integer from 0 to 5. In someembodiments, u is 0. In other embodiments, u is 1. In some embodiments,X¹ and X² are carbon. In other embodiments, X¹ is carbon and X² isnitrogen.

In some embodiments, the compound has the formula:

In Formulae (XIXA) and (XIXB), L¹, R⁴, R⁶, R⁸, R⁹, z, w and u are asdefined above. In some embodiments, w is 0. In other embodiments, wis 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substitutedor unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2to 6 membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R⁵ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R³⁷-substituted or unsubstituted C₁ to C₅ alkyl, or R³⁷-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³⁷ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁸ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R⁸ is hydrogen, —F, methyl or methoxy. In some embodiments,R³ is hydrogen.

In some embodiments, R⁹ is halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁰-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁰-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁰ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁹ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R⁹ is —F,methyl or methoxy. The symbol u is an integer from 0 to 5. In someembodiments, u is 0. In other embodiments, u is 1. In some embodiments,X¹ and X² are carbon. In other embodiments, X¹ is carbon and X² isnitrogen.

In some embodiments, the compound has the formula:

In Formulae (XXA) and (XXB), L¹, R², R⁴, R⁵, R⁶, R⁸, R⁹, z, w and u areas defined above. In some embodiments, w is 0. In other embodiments, wis 1. R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH, —NH₂,unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.As set forth above in Formulae (IIA), (IIB), (VA), (VB), (VIIIA),(VIIIB), (XIA), (XIB), (XIVA), (XIVB), (XVIIA) and (XVIIB) above, R² maybe joined together with R⁵ to form a substituted or unsubstituted (e.g.R⁶-substituted) heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures) or substituted (e.g. R¹⁶-substituted)or unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures). In some embodiments of Formulae (XXA) and(XXB), R² and R⁵ are not joined together to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹ substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is Oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R⁵ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R²⁸-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁸-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁸ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁵ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁵ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁵ is methoxy.

In some embodiments, R⁸ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R³⁷-substituted or unsubstituted C₁ to C₅ alkyl, or R³⁷-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³⁷ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁸ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R⁵ is hydrogen, —F, methyl or methoxy. In some embodiments,R⁵ is hydrogen.

In some embodiments, R⁹ is halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁰-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁰-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁰ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁹ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R⁹ is —F,methyl or methoxy. The symbol u is an integer from 0 to 5. In someembodiments, u is 0. In other embodiments, u is 1. In some embodiments,X¹ and X² are carbon. In other embodiments, X¹ is carbon and X² isnitrogen.

In some embodiments, the compound has the formula:

In Formulae (XXIA) and (XXIB), L¹, R², R⁴, R⁵, R⁶, R¹⁰, R¹², z and w areas defined above. In some embodiments, w is 0. In other embodiments, wis 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substitutedor unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2to 6 membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.

The symbol q is an integer from 0 to 5. As set forth above in Formulae(IIA), (IIB), (VA), (VB), (VIIIA), (VIIIB), (XIA), (XIB), (XIVA),(XIVB), (XVIIA), (XVIIB), (XXA) and (XXB) above, R² may be joinedtogether with R⁵ to form a substituted or unsubstituted (e.g.R⁶-substituted) heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures) or substituted (e.g. R¹⁶-substituted)or unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures). In some embodiments of Formulae (XXIA) and(XXIB), R² and R⁵ are not joined together to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. In some embodiments, R² is hydrogen or unsubstituted alkyl(e.g. C₁ to C₁₀ alkyl). In some embodiments, R² is hydrogen. In someembodiments, R² is methyl, ethyl, propyl, tertiary butyl, methylenecyclopropyl (—CH₂-cyclopropyl), methoxy, ethoxy, propoxy, butoxy or—CF₃. In some embodiments, R² is unsubstituted C₁ to C₅ alkyl. In someembodiments, R² is methyl. In some embodiments, R⁶ is halogen, —CN,—CF₃, —OH, —NH₂, R³¹-substituted or unsubstituted C₁ to C₅ alkyl, orR³¹-substituted or unsubstituted 2 to 6 membered heteroalkyl, whereinR³¹ is oxo, halogen, —CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl,unsubstituted 2 to 6 membered heteroalkyl. In some embodiments, R⁶ ismethoxy, ethoxy, propoxy, Cl, F or CF₃. In some embodiments, R⁶ ismethoxy, ethoxy, or propoxy. In some embodiments, R⁶ is methoxy. Thesymbol z is an integer from 0 to 4. In some embodiments, z is 0. Inother embodiments z is one. Where z is one, R⁶ may be attached to thephenyl ring para to the sulfonamide moiety. In other embodiments where zis one, R⁶ is attached to the phenyl ring meta to the sulfonamidemoiety.

In some embodiments, R⁵ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R²⁸-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁸-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁸ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁵ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁵ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁵ is methoxy.

In some embodiments, R¹⁰ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴³-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴³-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴³ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹⁰ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹⁰ is hydrogen, —F, methyl or methoxy. In someembodiments, R¹⁰ is hydrogen.

In some embodiments, R¹² is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁹-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹² is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹² is hydrogen, —F, methyl or methoxy. In someembodiments, R¹¹ is hydrogen.

R¹⁴ is independently halogen, —CN, —CF₃, —NR^(14A)—C(O)R^(14B),—NR^(14A)—C(O)—OR^(14B), —C(O)NR^(14A)R^(14B), —NR^(14A)S(O)₂R^(14B),—S(O)₂N(R^(14A))(R^(14B)), —SR^(14A), —S(O)R^(14B), —S(O)₂R^(14B),—NR^(14A)R^(14B), —OR^(14A), —C(O)R^(14B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(14A) and R^(14B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R¹⁴, R^(14A) and R^(14B) are substitutedsubstituents, R¹⁴, R^(14A) and R¹⁴ are independently substituted withR⁵⁵. For example, in some embodiments, R¹⁴, R^(14A) and R^(14B) areindependently R⁵⁵-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁵⁵-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁵⁵-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁵⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁵⁵-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁵⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R⁵⁵ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(55A)—C(O)R^(55B), —NR^(55A)—C(O)—OR^(55B),—C(O)NR^(55A)R^(55B), —NR^(55A)S(O)₂R^(55B), —S(O)₂N(R^(55A))(R^(55B)),—SR^(55A), —S(O)R^(55B), —S(O)₂R^(55B), —NR^(55A)R^(55B), —OR^(55A),—C(O)R^(55B), R⁵⁶-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁵⁶-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁵⁶-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁵⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁵⁶-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁵⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(55A) and R^(55B) are independently hydrogen, R⁵⁶-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁵⁶-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁵⁶-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁵⁶-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁵⁶-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁵⁶-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁵⁶ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(56A)—C(O)R^(56B), —NR^(56A)—C(O)—OR^(56B),—C(O)NR^(56A)R^(56B), —NR^(56A)S(O)₂R^(56B), —S(O)₂N(R^(56A))(R^(56B)),SR^(56A), S(O)R⁵⁶, —S(O)₂R^(56B), NR^(56A)R^(5B), OR^(56A), C(O)R⁵⁶,R⁵⁷-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R⁵⁷-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁵⁷-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁵⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁵⁷-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁵⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(56A) and R^(56B) are independently hydrogen, R⁵⁷-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁵⁷-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁵⁷-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁵⁷-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁵⁷-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁵⁷-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁵⁷ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(57A)—C(O)R^(57B), —NR^(57A)—C(O)—OR^(57B),—C(O)NR^(57A)R^(57B), —NR^(57A)S(O)₂R^(57B), —S(O)₂N(R^(57A))(R^(57B)),—SR^(57A), —S(O)R^(57B), —S(O)₂R^(57B), —NR^(57A)R^(57B), —OR^(57A),—C(O)R^(57B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(57A) and R^(57B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R¹⁴ is halogen, —CN, —CF₃, —OH, —NH₂,R⁵⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R⁵⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁵⁵ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹⁴ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R¹⁴ is-F,methyl or methoxy. In some embodiments, q is 0. In other embodiments, qis one.

In some embodiments, the compound has the formula:

In Formulae (XXIIA) and (XXIIB), R⁴, R⁶, R¹⁰, R¹², R¹⁴, L¹, q, w and zare as defined above. In some embodiments, w is 0. In other embodiments,w is 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substitutedor unsubstituted C₁ to C₅ alkyl, or R²⁵⁻substituted or unsubstituted 2to 6 membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.In some embodiments, R⁶ is halogen, —CN, —CF₃, —OH, —NH₂,R³¹-substituted or unsubstituted C₁ to C₅ alkyl, or R³¹ substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R³¹ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁶ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁶ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁶ is methoxy. The symbol z is an integerfrom 0 to 4. In some embodiments, z is 0. In other embodiments z is one.Where z is one, R⁶ may be attached to the phenyl ring para to thesulfonamide moiety. In other embodiments where z is one, R⁶ is attachedto the phenyl ring meta to the sulfonamide moiety.

In some embodiments, R¹⁰ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴³-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴³-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴³ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹⁰ is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹⁰ is hydrogen, —F, methyl or methoxy. In someembodiments, R¹⁰ is hydrogen.

In some embodiments, R¹² is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R⁴⁹-substituted or unsubstituted C₁ to C₅ alkyl, or R⁴⁹-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁴⁹ is OXo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹² is hydrogen, methyl,ethyl, propyl, —Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In someembodiments, R¹² is hydrogen, —F, methyl or methoxy. In someembodiments, R¹¹ is hydrogen.

In some embodiments, R¹⁴ is halogen, —CN, —CF₃, —OH, —NH₂,R⁵⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R⁵⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁵⁵ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹⁴ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R¹⁴ is-F,methyl or methoxy. In some embodiments, q is 0. In other embodiments, qis one.

In some embodiments, the compound has the formula:

In Formulae (XXIIIA) and (XXIIIB), R², R⁴, R⁵, R⁶, w and z are asdefined above. In some embodiments, w is 0. In other embodiments, wis 1. In some embodiments, L¹ is —NH—C(O)— as illustrated in Formula(IC1) or (IC2). R⁴ may be halogen, —CN, —CF₃, —OH, —NH₂, R²⁵-substitutedor unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted or unsubstituted 2to 6 membered heteroalkyl, wherein R²⁵ is oxo, halogen, —CN, —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is not F. In some embodiments, R⁴is not halogen. In some embodiments, R⁴ is —CF₃, —OH, —NH₂,R²⁵-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁵-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁵ is —CF₃, —OH,—NH₂, unsubstituted C₁ to C₅ alkyl, or unsubstituted 2 to 6 memberedheteroalkyl. In some embodiments, R⁴ is methyl, methoxy, —CF₃, or —OH.

The symbol t is an integer from 0 to 4. As set forth above in Formulae(IIA), (IIB), (VA), (VB), (VIIIA), (VIIIB), (XIA), (XIB), (XIVA),(XIVB), (XVIIA), (XVIIB), (XXA), (XXB), (XXIA) and (XXIB) above, R² maybe joined together with R⁵ to form a substituted or unsubstituted (e.g.R⁶-substituted) heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures) or substituted (e.g. R¹⁶-substituted)or unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures). In some embodiments of Formulae (XXIIIA) and(XXIIIB), R² and R⁵ are not joined together to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. In some embodiments, R² is hydrogen or unsubstituted alkyl(e.g. C₁ to C₁₀ alkyl). In some embodiments, R² is hydrogen. In someembodiments, R² is unsubstituted C₁ to C₅ alkyl. In some embodiments, R²is methyl. In some embodiments, R² is methyl, ethyl, propyl, tertiarybutyl, methylene cyclopropyl (—CH₂-cyclopropyl), methoxy, ethoxy,propoxy, butoxy or —CF₃. In some embodiments, R⁶ is halogen, —CN, —CF₃,—OH, —NH₂, R³¹-substituted or unsubstituted C₁ to C₅ alkyl, orR³¹-substituted or unsubstituted 2 to 6 membered heteroalkyl, whereinR³¹ is oxo, halogen, —CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl,unsubstituted 2 to 6 membered heteroalkyl. In some embodiments, R⁶ ismethoxy, ethoxy, propoxy, Cl, F or CF₃. In some embodiments, R⁶ ismethoxy, ethoxy, or propoxy. In some embodiments, R⁶ is methoxy. Thesymbol z is an integer from 0 to 4. In some embodiments, z is 0. Inother embodiments z is one. Where z is one, R⁶ may be attached to thephenyl ring para to the sulfonamide moiety. In other embodiments where zis one, R⁶ is attached to the phenyl ring meta to the sulfonamidemoiety.

R¹⁵ is independently halogen, —CN, —CF₃, —NR^(15A)—C(O)R^(15B),—NR^(15A)—C(O)—OR^(15B), —C(O)NR^(15A)R^(15B), —NR^(15A)S(O)₂R^(15B),—S(O)₂N(R^(15A))(R^(15B)), —SR^(15A), —S(O)R^(15B), —S(O)₂R^(15B),—NR^(5A)R^(15B), —OR^(5A), —C(O)R^(15B), substituted or unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), substitutedor unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C₃to C₁₄ cycloalkyl including fused ring structures), substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), or substitutedor unsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R^(15A) and R^(15B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R⁵, R^(15A) and R^(15B) are substitutedsubstituents, R¹⁵, R^(15A) and R¹⁵ are independently substituted withR⁵⁸. For example, in some embodiments, R¹⁵, R^(15A) and R^(15B) areindependently R⁵⁸-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁵⁸-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁵⁸-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁵⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁵⁸-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁵⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R⁵⁸ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(58A)—C(O)R^(58B), —NR^(8A)—C(O)—OR^(58B),—C(O)NR^(58A)R^(58B), —NR^(58A)S(O)₂R^(58B), —S(O)₂N(R^(58A))(R^(58B)),—SR^(58A), —S(O)R^(58B), —S(O)₂R^(58B), —NR^(58A)R^(58B), —OR^(58A),—C(O)R^(58B), R⁵⁹-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁵⁹-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁵⁹-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁵⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁵⁹-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁵⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(58A) and R^(58B) are independently hydrogen, R⁵⁹-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁵⁹-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁵⁹-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁵⁹-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁵⁹-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁵⁹-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁵⁹ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(59A)—C(O)R^(59B), —NR^(59A)—C(O)—OR^(59B),—C(O)NR^(59A)R^(59B), —NR^(59A)S(O)₂R^(59B), —S(O)₂N(R^(59A))(R^(59B)),—SR^(59A), —S(O)R^(59B), —S(O)₂R^(59B), —NR^(59A)R^(59B), —OR^(59A),—C(O)R^(59B), R⁶⁰ substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁶⁰-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁶⁰-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁶⁰-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁶⁰-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁶⁰-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(59A) and R^(59B) are independently hydrogen, R⁶⁰-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁶⁰-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁶⁰-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁶⁰-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁶⁰-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁶⁰-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁶⁰ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(60A)—C(O)R^(60B), —NR^(60A)—C(O)—OR^(6B),—C(O)NR^(60A)R^(60B), —NR^(60A)S(O)₂R^(60B), —S(O)₂N(R^(60A))(R^(60B)),—SR^(60A), —S(O)R^(60B), —S(O)₂R^(60B), —NR^(60A)R^(6B), —OR^(60A),—C(O)R^(60B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(60A) and R^(60B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R⁵ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,R²⁸-substituted or unsubstituted C₁ to C₅ alkyl, or R²⁸-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R²⁸ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁵ is methoxy, ethoxy,propoxy, Cl, F or CF₃. In some embodiments, R⁵ is methoxy, ethoxy, orpropoxy. In some embodiments, R⁵ is methoxy.

In some embodiments, R¹⁵ is halogen, —CN, —CF₃, —OH, —NH₂,R⁵⁸-substituted or unsubstituted C₁ to C₅ alkyl, or R⁵⁸-substituted orunsubstituted 2 to 6 membered heteroalkyl, wherein R⁵⁸ is oxo, halogen,—CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R¹⁵ is methyl, ethyl, propyl,—Cl, —F, —CF₃, methoxy, ethoxy, propoxy. In some embodiments, R¹⁵ is-F,methyl or methoxy. In some embodiments, t is 0. In other embodiments, tis one.

In another aspect, the compound has the formula:

In Formula (XXIV), R⁶⁶ and R⁶⁷ are independently substituted orunsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures). In someembodiments, R⁶⁶ and R⁶⁷ are independently substituted or unsubstitutedheteroaryl (e.g. 5 to 14 membered heteroaryl including fused ringsstructures). In some embodiments, R⁶⁶ and R⁶⁷ are independentlysubstituted or unsubstituted phenyl.

In some embodiments, where R⁶⁶ and R⁶⁷ are substituted substituents, R⁶⁶and R⁶⁷ are independently substituted with R⁷⁴. For example, in someembodiments, R⁶⁶ and R⁶⁷ are independently R⁷⁴-substituted orunsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures) or R⁷⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

R⁷⁴ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(74A)—C(O)R^(74B), —NR^(74A)—C(O)—OR^(74B),—C(O)NR^(74A)R^(74B), —NR^(74A)S(O)₂R^(74B), —S(O)₂N(R^(74A))(R^(74B)),—SR^(74A), —S(O)R^(74B), —S(O)₂R^(74B), NR^(74A)R^(74B), —OR^(74A),C(O)R^(74B), R⁷⁵-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), R⁷⁵-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁷⁵-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁷⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁷⁵-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁷⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(74A) and R^(74B) are independently hydrogen, R⁷⁵-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁷⁵-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁷⁵-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁷⁵-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁷⁵-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁷⁵-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁷⁵ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(75A)—C(O)R^(75B), —NR^(75A)—C(O)—OR^(75B),—C(O)NR^(75A)R^(75B), —NR^(75A)S(O)₂R^(75B), —S(O)₂N(R^(75A))(R^(75B)),—SR^(75A), S(O)R^(75B), —S(O)₂R^(75B), NR^(75A)R^(75B), —OR^(75A),—C(O)R^(75B), R⁷⁶-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁷⁶-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁷⁶-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁷⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁷⁶-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁷⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(75A) and R^(75B) are independently hydrogen, R⁷⁶-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁷⁶-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁷⁶-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁷⁶-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁷⁶-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁷⁶-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁷⁶ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(76A)—C(O)R^(76B), —NR^(76A)—C(O)—OR^(76B),—C(O)NR^(76A)R^(76B), —NR^(76A)S(O)₂R^(76B), —S(O)₂N(R^(76A))(R^(76B)),—SR^(76A), —S(O)R^(76B), —S(O)₂R^(76B), —NR^(6A)R^(76B), —OR^(76A),—C(O)R^(76B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(76A) and R^(76B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R⁶⁶ and R⁶⁷ are independently R⁷⁴-substituted orunsubstituted phenyl. In some embodiments, R⁶⁶ and R⁶⁷ are independentlyR⁷⁴-substituted or unsubstituted phenyl, wherein R⁷⁴ is independentlyhydrogen, halogen, —CN, —CF₃, —OH, —NH₂, R⁷⁵-substituted orunsubstituted C₁ to C₅ alkyl, or R⁷⁵-substituted or unsubstituted 2 to 6membered heteroalkyl, wherein R⁷⁵ is independently oxo, halogen, —CN,—CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl, unsubstituted 2 to 6membered heteroalkyl. In some embodiments, R⁷⁴ is independentlyhydrogen, methyl, ethyl, propyl, tertiary butyl, —Cl, —F, —CF₃, methoxy,ethoxy, propoxy. In some embodiments, R⁷⁴ is independently hydrogen, —F,methyl or methoxy. In some embodiments, R⁷⁴ is hydrogen.

R⁶⁸, R⁶⁹ and R⁷⁰ are independently hydrogen, halogen, —CN, —CF₃,—NR^(68A)—C(O)R^(68B), —NR^(68A)—C(O)—OR^(6B), —C(O)NR^(68A)R^(68B),—NR^(68A)S(O)₂R^(68B), —S(O)₂N(R^(68A))(R^(68B)), —SR^(68A),—S(O)R^(68B), —S(O)₂R^(68B), —NR^(68A)R^(68B), —OR^(68A), —C(O)R^(68B),substituted or unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), substituted or unsubstituted heteroalkyl (e.g.substituted or unsubstituted 2 to 20 membered heteroalkyl), substitutedor unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fusedring structures), substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fusedring structures), or substituted or unsubstituted heteroaryl (e.g. 5 to14 membered heteroaryl including fused rings structures).

R^(68A) and R^(68B) are independently hydrogen, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, R⁶⁸, R⁶⁹, and R⁷⁰ are independently hydrogen,substituted or unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), substituted or unsubstituted heteroalkyl (e.g.substituted or unsubstituted 2 to 20 membered heteroalkyl), substitutedor unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fusedring structures), substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fusedring structures), or substituted or unsubstituted heteroaryl (e.g. 5 to14 membered heteroaryl including fused rings structures). In someembodiments, R⁶⁸, R⁶⁹, and R⁷⁰ are independently hydrogen, substitutedor unsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀alkyl), or substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl). In some embodiments, R⁷⁰ ishydrogen, substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), or substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl) and R⁶⁸ and R⁶⁹ are independently substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),or substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl). In some embodiments, R⁷⁰ ishydrogen. In some embodiments, R⁶⁸ and R⁶⁹ are independently substitutedor unsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀alkyl). In some embodiments, R⁶⁸ and R⁶⁹ are independently substitutedor unsubstituted C₁ to C₁₀ alkyl. In some embodiments, R⁶⁸ and R⁶⁹ areindependently substituted or unsubstituted C₁ to C₅ alkyl. In someembodiments, R⁶⁸ and R⁶⁹ are independently methyl, ethyl, propyl, ortertiary butyl.

In some embodiments, where R⁶⁸, R⁶⁹, R⁷⁰, R⁴, R^(68A) and R^(68B) aresubstituted substituents, R⁶⁸, R⁶⁹, R⁷⁰, R⁴, R^(68A) and R^(68B) areindependently substituted with R⁷⁷. For example, in some embodiments,R⁶⁸, R⁶⁹, R⁷⁰, R⁴, R^(68A) and R^(68B) are independently R⁷⁷-substitutedor unsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀alkyl), R⁷⁷-substituted or unsubstituted heteroalkyl (e.g. substitutedor unsubstituted 2 to 20 membered heteroalkyl), R⁷⁷-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁷⁷-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁷⁷-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁷⁷-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁷⁷ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(77A)—C(O)R^(77B), —NR^(77A)—C(O)—OR^(77B),—C(O)NR^(77A)R^(77B), —NR^(77A)S(O)₂R^(77B), —S(O)₂N(R^(77A))(R^(77B)),—SR^(77A), —S(O)R^(77B), —S(O)₂R^(77B), —NR^(77A)R^(77B), —OR^(77A),—C(O)R^(77B), R⁷⁸-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁷⁸-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁷⁸-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁷⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁷⁸-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁷⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(77A) and R^(77B) are independently hydrogen, R⁷⁸-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁷⁸-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁷⁸-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁷⁸-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁷⁸-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁷⁸-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁷⁸ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(78A)—C(O)R^(78B), —NR^(78A)—C(O)—OR^(78B),—C(O)NR^(78A)R^(78B), —NR^(78A)S(O)₂R^(78B), —S(O)₂N(R^(78A))(R^(78B)),—SR^(78A), —S(O)R^(78B), —S(O)₂R^(78B), —NR^(78A)R^(78B), —OR^(78A),—C(O)R^(78B), R⁷⁹ substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁷⁹-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁷⁹-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁷⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁷⁹-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁷⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(78A) and R^(78B) are independently hydrogen, R⁷⁹-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁷⁹-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁷⁹-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁷⁹-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁷⁹-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁷⁹-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁷⁹ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(79A)—C(O)R^(79B), —NR^(79A)—C(O)—OR^(79B),—C(O)NR^(79A)R^(79B), —NR^(79A)S(O)₂R^(79B), —S(O)₂N(R^(79A))(R^(79B)),—SR^(79A), —S(O)R^(79B), —S(O)₂R^(79B), —NR^(79A)R^(79B), —OR^(79A),—C(O)R^(79B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(79A) and R^(79B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R⁶⁸ and R⁶⁹ are independently halogen, —CN, —CF₃,—OH, —NH₂, R⁷⁷-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl) or R⁷⁷-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl). R⁶⁸ and R⁶⁹ may also independently be R⁷⁷-substituted orunsubstituted C₁ to C₁₀ alkyl. R⁶⁸ and R⁶⁹ may also independently beR⁷⁷-substituted or unsubstituted C₁ to C₅ alkyl.

In some embodiments, R⁷⁰ are independently hydrogen, halogen, —CN, —CF₃,—OH, —NH₂, R⁷⁷-substituted or unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl) or R⁷⁷-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl). R⁷⁰ may also independently be hydrogen, R⁷⁷-substituted orunsubstituted C₁ to C₁₀ alkyl. R⁷⁰ may also independently be hydrogen orR⁷⁷-substituted or unsubstituted C₁ to C₅ alkyl.

L⁶ is -L⁷-N(R⁷¹)—C(O)—N(R⁷²)-L⁸-, -L⁷-N(R⁶¹)—C(O)-L⁸- or-L⁷-C(O)—N(R⁷¹)-L⁸-. L⁷ and L⁸ are independently a bond or substitutedor unsubstituted alkylene (e.g. substituted or unsubstituted C₁ to C₂₀alkylene). In some embodiments, L⁷ and L⁸ are independently a bond orsubstituted or unsubstituted C₁ to C₁₀ alkylene. In other embodiments,L⁷ and L⁸ are independently a bond or substituted or unsubstituted C₁ toC₅ alkylene. L⁷ and L⁸ may also independently be a bond or unsubstitutedmethylene. In some embodiments, L⁷ and L⁸ are a bond.

In some embodiments, where L⁷ and L⁸ are substituted, L⁷ and L⁸ areindependently substituted with R⁷³. For example, in some embodiments, L⁷and L⁸ are independently R⁷³-substituted or unsubstituted alkyl (e.g.substituted or unsubstituted C₁ to C₂₀ alkyl). R⁷³ is independently oxo(where permitted according to valency rules), halogen, —CN, —CF₃,—NR^(73A)—C(O)R^(73B), —NR^(73A)—C(O)—OR^(73B), —C(O)NR^(73A)R^(73B),—NR^(73A)S(O)₂R^(73B), —S(O)₂N(R^(73A))(R^(73B)), —SR^(73A),—S(O)R^(73B), —S(O)₂R^(73B), —NR^(73A)R^(73B), —OR^(73A), —C(O)R^(73B),unsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),unsubstituted heteroalkyl (e.g. substituted or unsubstituted 2 to 20membered heteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄cycloalkyl including fused ring structures), unsubstitutedheterocycloalkyl (e.g. 3 to 14 membered heterocycloalkyl including fusedring structures), unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures). R^(73A) andR^(73B) are independently hydrogen, unsubstituted alkyl (e.g.substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstituted heteroalkyl(e.g. substituted or unsubstituted 2 to 20 membered heteroalkyl),unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), unsubstituted heterocycloalkyl (e.g. 3 to 14 memberedheterocycloalkyl including fused ring structures), unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orunsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

R⁷¹ and R⁷² are independently hydrogen, —CN, —CF₃, substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 14membered heterocycloalkyl including fused ring structures), substitutedor unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or substituted or unsubstituted heteroaryl (e.g. 5 to 14membered heteroaryl including fused rings structures).

In some embodiments, where R⁷¹ and R⁷² are a substituted substituent,R⁷¹ and R⁷² are independently substituted with R⁸⁰. For example, in someembodiments, R⁷¹ and R⁷² are independently R⁸⁰-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁸⁰-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁸⁰-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁸⁰-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁸⁰-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁸⁰-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁸⁰ is oxo (where permitted according to valency rules), halogen, —CN,—CF₃, —NR^(80A)—C(O)R^(80B), —NR^(80A)—C(O)—OR^(80B),—C(O)NR^(80A)R^(80B), —NR^(80A)S(O)₂R^(80B), —S(O)₂N(R^(80A))(R^(80B)),—SR^(80A), —S(O)R^(80B), —S(O)₂R^(80B), —NR^(80A)R^(80B), —OR^(80A),—C(O)R^(80B), R⁸¹-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁸¹-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁸¹-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁸¹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁸¹-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁸¹-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(80A) and R^(80B) are independently hydrogen, R⁸¹-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁸¹-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁸¹-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁸¹-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁸¹-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁸¹-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁸¹ is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(81A)—C(O)R^(81B), —NR^(81A)—C(O)—OR^(81B),—C(O)NR^(81A)R^(81B), —NR^(81A)S(O)₂R^(81B), —S(O)₂N(R^(81A))(R^(81B)),—SR^(81A), —S(O)R^(81B), —S(O)₂R^(81B), —NR^(81A)R^(81B), —OR^(81A),—C(O)R^(81B), R⁸²-substituted or unsubstituted alkyl (e.g. substitutedor unsubstituted C₁ to C₂₀ alkyl), R⁸²-substituted or unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), R⁸²-substituted or unsubstituted cycloalkyl (e.g. C₃ toC₁₄ cycloalkyl including fused ring structures), R⁸²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), R⁸²-substituted or unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orR⁸²-substituted or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

R^(81A) and R^(81B) are independently hydrogen, R⁸²-substituted orunsubstituted alkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl),R⁸²-substituted or unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), R⁸²-substituted orunsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), R⁸²-substituted or unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),R⁸²-substituted or unsubstituted aryl (e.g. a C₆ to C₁₄ aryl includingfused ring structures), or R⁸²-substituted or unsubstituted heteroaryl(e.g. 5 to 14 membered heteroaryl including fused rings structures).

R⁸² is independently oxo (where permitted according to valency rules),halogen, —CN, —CF₃, —NR^(2A)—C(O)R^(2B), —NR^(2A)—C(O)—OR^(82B),—C(O)NR^(2A)R^(2B), —NR^(2A)S(O)₂R^(2B), —S(O)₂N(R^(82A))(R^(92B)),—SR^(82A), —S(O)R^(82B), —S(O)₂R^(82B), —NR^(82A)R^(82B), —OR^(82A),—C(O)R^(82B), unsubstituted alkyl (e.g. substituted or unsubstituted C₁to C₂₀ alkyl), unsubstituted heteroalkyl (e.g. substituted orunsubstituted 2 to 20 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃ to C₁₄ cycloalkyl including fused ring structures),unsubstituted heterocycloalkyl (e.g. 3 to 14 membered heterocycloalkylincluding fused ring structures), unsubstituted aryl (e.g. a C₆ to C₁₄aryl including fused ring structures), or unsubstituted heteroaryl (e.g.5 to 14 membered heteroaryl including fused rings structures).

R^(82A) and R^(82B) are independently hydrogen, unsubstituted alkyl(e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures).

In some embodiments, R⁷¹ and R⁷² are independently hydrogen, halogen,—CN, —CF₃, —OH, —NH₂, R⁸⁰-substituted or unsubstituted C₁ to C₅ alkyl,or R⁸⁰-substituted or unsubstituted 2 to 6 membered heteroalkyl, whereinR⁸⁰ is oxo, halogen, —CN, —CF₃, —OH, —NH₂, unsubstituted C₁ to C₅ alkyl,unsubstituted 2 to 6 membered heteroalkyl, or unsubstituted C₃ to C₆cycloalkyl (e.g. cyclopropyl). In some embodiments, R⁷¹ and R⁷² areindependently hydrogen, methyl, ethyl, propyl, tertiary butyl, orcyclopropyl methylene (—CH₂-cyclopropyl). In some embodiments, R⁶¹ andR⁶² are hydrogen.

L⁴ and L⁵ are independently a bond or substituted or unsubstitutedalkylene (e.g. substituted or unsubstituted C₁ to C₂₀ alkylene). In someembodiments, L⁴ and L⁵ are independently a bond or substituted orunsubstituted C₁ to C₁₀ alkylene. In other embodiments, L⁴ and L⁵ areindependently a bond or unsubstituted C₁ to C₅ alkylene. L⁴ and L⁵ mayalso independently be a bond or unsubstituted methylene. In someembodiments, L⁵ is a bond and L⁴ is substituted or unsubstitutedalkylene (e.g. substituted or unsubstituted C₁ to C₂₀ alkylene). In someembodiments, L⁵ is a bond and L⁴ is unsubstituted C₁ to C₅ alkylene. Insome embodiments, L⁵ is a bond and L⁴ is unsubstituted methylene.

In some embodiments, where L⁴ and L⁵ are substituted, L⁴ and L⁵ areindependently substituted with R⁸³. For example, in some embodiments, L⁴and L⁵ are independently R⁸³-substituted or unsubstituted alkyl (e.g.substituted or unsubstituted C₁ to C₂₀ alkyl). R⁸³ is independently oxo(where permitted according to valency rules), halogen, —CN, —CF₃,—NR^(3A)—C(O)R^(83B), —NR^(3A)—C(O)—OR^(83B), —C(O)NR^(3A)R^(83B),—NR^(3A)S(O)₂R^(83B), —S(O)₂N(R^(83A))(R^(83B)), —SR^(3A), —S(O)R^(3B),—S(O)₂R^(3B), —NR^(83A), R^(3B), —OR^(3A), —C(O)R^(3B), unsubstitutedalkyl (e.g. substituted or unsubstituted C₁ to C₂₀ alkyl), unsubstitutedheteroalkyl (e.g. substituted or unsubstituted 2 to 20 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkylincluding fused ring structures), unsubstituted heterocycloalkyl (e.g. 3to 14 membered heterocycloalkyl including fused ring structures),unsubstituted aryl (e.g. a C₆ to C₁₄ aryl including fused ringstructures), or unsubstituted heteroaryl (e.g. 5 to 14 memberedheteroaryl including fused rings structures). R^(83A) and R^(83B) areindependently hydrogen, unsubstituted alkyl (e.g. substituted orunsubstituted C₁ to C₂₀ alkyl), unsubstituted heteroalkyl (e.g.substituted or unsubstituted 2 to 20 membered heteroalkyl),unsubstituted cycloalkyl (e.g. C₃ to C₁₄ cycloalkyl including fused ringstructures), unsubstituted heterocycloalkyl (e.g. 3 to 14 memberedheterocycloalkyl including fused ring structures), unsubstituted aryl(e.g. a C₆ to C₁₄ aryl including fused ring structures), orunsubstituted heteroaryl (e.g. 5 to 14 membered heteroaryl includingfused rings structures).

In some embodiments, each substituted group described above in thecompounds of Formulae (IA) to (XXIIIA), (IB) to (XXIIIB) and (XXIV) issubstituted with at least one substituent group. More specifically, insome embodiments, each substituted alkyl, substituted heteroalkyl,substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl,and/or substituted heteroaryl described above in the compounds ofFormulae (IA) to (XXIIIA), (IB) to (XXIIIB) and (XXIV) are substitutedwith at least one substituent group. In other embodiments, at least oneor all of these groups are substituted with at least one size-limitedsubstituent group. Alternatively, at least one or all of these groupsare substituted with at least one lower substituent group.

In other embodiments of the compounds of Formulae (IA) to (XXIIIA), (IB)to (XXIIIB) and (XXIV), each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₂₀ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₈ cycloalkyl, and/or each substitutedor unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to8 membered heterocycloalkyl.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₅ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₅-C₇ cycloalkyl, and/or each substitutedor unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to7 membered heterocycloalkyl.

In another embodiment, the compounds useful in the methods andpharmaceutical compositions disclosed herein include any one or all ofthe compounds set forth in Table 1 and Table 2. In another embodiment,the compounds useful in the methods and pharmaceutical compositionsdisclosed herein include any one or all of the compounds set forth inTable 1. In another embodiment, the compounds useful in the methods andpharmaceutical compositions disclosed herein include any one or all ofthe compounds set forth in Table 2. In another embodiment, the compoundsuseful in the methods and pharmaceutical compositions disclosed hereininclude any one or all of the compounds set forth in Examples 2 to 61.In some related embodiments, the compounds useful in the methods andpharmaceutical compositions disclosed herein do not include thecompounds set forth in Example 62. In some related embodiments, thecompounds useful in the methods and pharmaceutical compositionsdisclosed herein do not include the following compound:

III. Methods

In one aspect, a method of reducing a Wnt-mediated effect on a cell isprovided. The method includes contacting the cell with an effectiveamount of a compound as set forth herein (e.g., Section II above orExamples below, such as Formulae (IA) to (XXIIIA), (IB) to (XXIIIB) and(XXIV) and embodiments thereof). For example, the method of reducing aWnt-mediated effect on a cell may include contacting the cell with aneffective amount of a compound of Formula (IA) or (TB) as defined above,including embodiments thereof. Thus, any of the Formulae or embodimentsthereof set forth above may be applicable to the method of reducing aWnt-mediated effect on a cell. The Wnt-mediated effect on a cell isreduced relative the amount of Wnt-meditated effect on the cell in theabsence of the compound.

In one embodiment, the Wnt-mediated effect is an increase in degradationof Pygopus (relative to the degradation of Pygopus in the absence of thecompound), an increase in degradation of non-oncogenic beta-Catenin(relative to the degradation of beta-Catenin in the absence of thecompound), a decrease in degradation of Axin (relative to thedegradation of Axin in the absence of the compound), a decrease inactivity of Myc (relative to the activity of Myc in the absence of thecompound), a decrease in activity of CD44 (relative to the activity ofCD44 in the absence of the compound), a decrease in activity of Axin2(relative to the activity of Axin 2 in the absence of the compound), adecrease in activity of Bcl-9 (relative to the activity of Bcl-9 in theabsence of the compound), and/or a decrease in activity of cyclin D(relative to the activity of cyclin D in the absence of the compound).These Wnt-mediated effects may be assessed using standard assays knownin the art.

In another aspect, a method of treating cancer in a subject in needthereof is provided. The method includes administering to the subject aneffective amount of a compound as set forth herein (e.g., Section IIabove or Examples below, such as. Formulae (IA) to (XXIIIA), (IB) to(XXIIIB) and (XXIV) and embodiments thereof), or pharmaceuticallyacceptable salt thereof. The compound may optionally be administeredwith a pharmaceutically acceptable excipient. Therefore, the compoundmay be administered as a pharmaceutical composition as set forth below.For example, the method of treating cancer may include administering tothe subject an effective amount of a compound of Formula (IB) or (IA) asdefined above, including embodiments thereof. Thus, any of the Formulaeor embodiments thereof set forth above may be applicable to the methodof treating cancer.

In some embodiments, the cancer is colon cancer, breast cancer, gastriccancer, brain cancer, head and neck cancer, liver cancer, lung cancer,lymphoma, melanoma, pancreatic cancer or prostate cancer. In someembodiment, the subject is a mammalian subject. In certain embodiments,the subject is a human subject (e.g. a cancer patient). Moreover, thecompound may be administered in conjunction with other known cancertherapies, including known chemotherapeutic compounds.

IV. Pharmaceutical Compositions

In another aspect, the present invention provides a pharmaceuticalcomposition including a pharmaceutically acceptable excipient and acompound as set forth herein (e.g., Section II above or Examples below,such as Formulae (IA) to (XXIIIA), Formulae (IB) to (XXIIIB) and(XXIV)). In some embodiments, the pharmaceutical composition includes atherapeutically effective amount of the compound. Desired therapeuticresults are described above in the Methods section.

For example, in some embodiments, the pharmaceutical compositionincludes a pharmaceutically acceptable excipient and a compound ofFormula (IIA) or (IIB) or embodiments thereof. In other embodiments, thepharmaceutical composition includes a pharmaceutically acceptableexcipient and a compound of Formula (IIIA) or (IIIB) or embodimentsthereof. In other embodiments, the pharmaceutical composition includes apharmaceutically acceptable excipient and a compound of Formula (IVA) or(IVB) or embodiments thereof. In other embodiments, the pharmaceuticalcomposition includes a pharmaceutically acceptable excipient and acompound of Formula (VA) or (VB) or embodiments thereof. In otherembodiments, the pharmaceutical composition includes a pharmaceuticallyacceptable excipient and a compound of Formula (VIA) or (VIB) orembodiments thereof. In other embodiments, the pharmaceuticalcomposition includes a pharmaceutically acceptable excipient and acompound of Formula (VIIA) or (VIIB) or embodiments thereof. In otherembodiments, the pharmaceutical composition includes a pharmaceuticallyacceptable excipient and a compound of Formula (VIIIA) or (VIIIB) orembodiments thereof. In other embodiments, the pharmaceuticalcomposition includes a pharmaceutically acceptable excipient and acompound of Formula (IXA) or (IXB) or embodiments thereof. In otherembodiments, the pharmaceutical composition includes a pharmaceuticallyacceptable excipient and a compound of Formula (XA) or (XB) orembodiments thereof. In other embodiments, the pharmaceuticalcomposition includes a pharmaceutically acceptable excipient and acompound of Formula (XIA) or (XIB) or embodiments thereof. In otherembodiments, the pharmaceutical composition includes a pharmaceuticallyacceptable excipient and a compound of Formula (XIIA) or (XIIB) orembodiments thereof. In other embodiments, the pharmaceuticalcomposition includes a pharmaceutically acceptable excipient and acompound of Formula (XIIIA) or (XIIIB) or embodiments thereof. In otherembodiments, the pharmaceutical composition includes a pharmaceuticallyacceptable excipient and a compound of Formula (XIVA) or (XIVB) orembodiments thereof. In other embodiments, the pharmaceuticalcomposition includes a pharmaceutically acceptable excipient and acompound of Formula (XVA) or (XVB) or embodiments thereof. In otherembodiments, the pharmaceutical composition includes a pharmaceuticallyacceptable excipient and a compound of Formula (XVIA) or (XVIB) orembodiments thereof. In other embodiments, the pharmaceuticalcomposition includes a pharmaceutically acceptable excipient and acompound of Formula (XXIV) or embodiments thereof.

As described above, pharmaceutical compositions are provided thatinclude the compound and pharmaceutically acceptable excipient, forexample, in admixture with a pharmaceutically acceptable excipient. Oneof skill in the art will recognize that the pharmaceutical compositionsmay include the pharmaceutically acceptable salts of the compoundsdescribed herein (e.g. in Section II).

In therapeutic and/or diagnostic applications, the compounds of theinvention can be formulated for a variety of modes of administration,including systemic and topical or localized administration. Techniquesand formulations generally may be found in Remington: The Science andPractice of Pharmacy (20^(th) ed.) Lippincott, Williams & Wilkins(2000).

The compounds disclosed herein are effective over a wide dosage range.The exact dosage will depend upon the route of administration, the formin which the compound is administered, the subject to be treated, thebody weight of the subject to be treated, and the preference andexperience of the attending physician.

Pharmaceutically acceptable salts are generally well known to those ofordinary skill in the art, and may include, by way of example but notlimitation, acetate, benzencsulfonatc, besylatc, benzoate, bicarbonate,bitartrate, bromide, calcium cdetatc, carnsylate, carbonate, citrate,edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate,napsylate, nitrate, pamoate (embonate), pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Otherpharmaceutically acceptable salts may be found in, for example,Remington: The Science and Practice of Pharmacy (20^(th) ed.)Lippincott, Williams & Wilkins (2000). Preferred pharmaceuticallyacceptable salts include, for example, acetate, benzoate, bromide,carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate,mesylate, napsylate, pamoate (embonate), phosphate, salicylate,succinatc, sulfate, or tartrate.

Depending on the specific conditions being treated, such agents may beformulated into liquid or solid dosage forms and administeredsystemically or locally. The agents may be delivered, for example, in atimed- or sustained-low release form as is known to those skilled in theart. Techniques for formulation and administration may be found inRemington: The Science and Practice of Pharmacy (20^(th) ed.)Lippincott, Williams & Wilkins (2000). Suitable routes may include oral,buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal,transmucosal, nasal or intestinal administration; parenteral delivery,including intramuscular, subcutaneous, intramedullary injections, aswell as intrathecal, direct intraventricular, intravenous,intra-articullar, intra-sternal, intra-synovial, intra-hepatic,intralesional, intracranial, intraperitoneal, intranasal, or intraocularinjections or other modes of delivery.

For injection, the agents of the invention may be formulated and dilutedin aqueous solutions, such as in physiologically compatible buffers suchas Hank's solution, Ringer's solution, or physiological saline buffer.For such transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art.

Use of pharmaceutically acceptable inert carriers to formulate thecompounds herein disclosed for the practice of the invention intodosages suitable for systemic administration is within the scope of theinvention. With proper choice of carrier and suitable manufacturingpractice, the compositions of the present invention, in particular,those formulated as solutions, may be administered parenterally, such asby intravenous injection. The compounds can be formulated readily usingpharmaceutically acceptable carriers well known in the art into dosagessuitable for oral administration. Such carriers enable the compounds ofthe invention to be formulated as tablets, pills, capsules, liquids,gels, syrups, slurries, suspensions and the like, for oral ingestion bya subject (e.g. patient) to be treated.

For nasal or inhalation delivery, the agents of the invention may alsobe formulated by methods known to those of skill in the art, and mayinclude, for example, but not limited to, examples of solubilizing,diluting, or dispersing substances such as, saline, preservatives, suchas benzyl alcohol, absorption promoters, and fluorocarbons.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in aneffective amount to achieve its intended purpose. Determination of theeffective amounts is well within the capability of those skilled in theart, especially in light of the detailed disclosure provided herein.

In addition to the active ingredients, these pharmaceutical compositionsmay contain suitable pharmaceutically acceptable carriers comprisingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Thepreparations formulated for oral administration may be in the form oftablets, dragees, capsules, or solutions.

Pharmaceutical preparations for oral use can be obtained by combiningthe active compounds with solid excipients, optionally grinding aresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations, for example, maize starch, wheat starch, rice starch,potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethyl-cellulose (CMC),and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegratingagents may be added, such as the cross-linked polyvinylpyrrolidone,agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol (PEG), and/or titanium dioxide, lacquer solutions, and suitableorganic solvents or solvent mixtures. Dye-stuffs or pigments may beadded to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin, and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols (PEGs). In addition, stabilizers may be added.

Depending upon the particular condition, or disease state, to be treatedor prevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may be administeredtogether with the inhibitors of this invention. For example,chemotherapeutic agents or other anti-proliferative agents may becombined with the inhibitors of this invention to treat proliferativediseases and cancer. Examples of known chemotherapeutic agents include,but are not limited to, adriamycin, dexamethasone, vincristine,cyclophosphamide, fluorouracil, topotecan, taxol, interferons, andplatinum derivatives.

Other examples of agents the compounds of this invention may also becombined with include, without limitation, anti-inflammatory agents suchas corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; agents for treating diabetessuch as insulin, insulin analogues, alpha glucosidase inhibitors,biguanides, and insulin sensitizers; and agents for treatingimmunodeficiency disorders such as gamma globulin.

These additional agents may be administered separately, as part of amultiple dosage regimen, from the composition. Alternatively, theseagents may be part of a single dosage form, mixed together with thecompound in a single composition.

Dosage forms (compositions) suitable for internal administration containfrom about 1.0 milligram to about 5000 milligrams of active ingredientper unit. In these pharmaceutical compositions, the active ingredientmay be present in an amount of about 0.5 to about 95% by weight based onthe total weight of the composition. Another convention for denoting thedosage form is in mg per meter squared (mg/m²) of body surface area(BSA). Typically, an adult will have approximately 1.75 m² of BSA. Basedon the body weight of the patient, the dosage may be administered in oneor more doses several times per day or per week. Multiple dosage unitsmay be required to achieve a therapeutically effective amount. Forexample, if the dosage form is 1000 mg, and the patient weighs 40 kg,one tablet or capsule will provide a dose of 25 mg per kg for thatpatient. It will provide a dose of only 12.5 mg/kg for a 80 kg patient.

By way of general guidance, for humans a dosage of as little as about 1milligrams (mg) per kilogram (kg) of body weight and up to about 10000mg per kg of body weight is suitable as a therapeutically effectivedose. Preferably, from about 5 mg/kg to about 2500 mg/kg of body weightis used. Other preferred doses range between 25 mg/kg to about 1000mg/kg of body weight. However, a dosage of between about 2 milligrams(mg) per kilogram (kg) of body weight to about 400 mg per kg of bodyweight is also suitable for treating some cancers.

Intravenously, the most preferred rates of administration can range fromabout 1 to about 1000 mg/kg/minute during a constant rate infusion. Apharmaceutical composition of the present invention can be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three, or four times daily. The composition isgenerally given in one or more doses on a daily basis or from one tothree times a week.

The present invention is not to be limited in scope by the exemplifiedembodiments, which are intended as illustrations of single aspects ofthe invention. Indeed, various modifications of the invention inaddition to those described herein will become apparent to those havingskill in the art from the foregoing description. Such modifications areintended to fall within the scope of the invention. Moreover, any one ormore features of any embodiment of the invention may be combined withany one or more other features of any other embodiment of the invention,without departing from the scope of the invention. For example, thecompounds described above are equally applicable to the methods andpharmaceutical compositions described herein. References citedthroughout this application are incorporated by reference herein intheir entirety for all purposes, whether previously specificallyincorporated or not.

V. Examples

The following examples are intended to illustrate certain embodiments ofthe invention and not to limit the scope of the invention.

Exemplary Syntheses.

Synthesis of compounds useful for the methods described herein generallyfollowed synthetic routes known in the art and/or described herein.Using chemical techniques known in the art and the teaching providedherein, a person having ordinary skill in the art will immediatelyunderstand appropriate synthesis routes to the compounds disclosedherein (e.g. the Formulae and embodiments disclosed in Section II). Anexemplary synthetic is shown below in Scheme 1.

Scheme 1 (Method A).

A solution of the acid (1 equiv) in MeOH (10 vol) was cooled to 0° C.and the amine (3 equiv) was added. The reaction mixture was stirred at0° C. for 1 hour and 14 hours at room temperature. The reaction mixturewas concentrated and partitioned between EtOAc and 0.5 M HCl solution.The organics were separated and dried over MgSO₄. The resulting darksolid was partitioned between Et₂O and 0.5 M NaOH solution. The aqueouslayer was separated and acidified to pH=1 with cone. HCl. The resultingsuspension was extracted with EtOAc. The organic layers were combined,dried over MgSO₄ and concentrated. The resulting solid was trituratedwith diethyl ether to provide the desired acid.

Scheme 1 (Method B).

To a solution of the acid (1.2 equiv), the amine (1 equiv), and HOBt(1.5 equiv) in DMF (5 vol) was added DIPEA (2.5 equiv) and EDC (1.5equiv). The reaction mixture was stirred at room temperature for 48hours. The reaction mixture was concentrated, partitioned between EtOAcand 5% lithium chloride solution. The organic layers were combined,dried over MgSO₄ and concentrated. The resulting dark oil was purifiedby column chromatography.

Scheme 1 (Method C).

To a solution of the acid (1.2 equiv) and the amine (1 equiv) in DMF (5vol) was added DIPEA (3 equiv) and pybop (1.5 equiv). The reactionmixture was stirred at room temperature or 40° C. for 48-96 hours. Thereaction mixture was concentrated and partitioned between EtOAc and 5%lithium chloride solution. The organic layers were combined, dried overMgSO₄ and concentrated. The resulting dark oil was purified by columnchromatography.

Acids useful in the synthesis of compounds described herein areexemplified, but not limited to, the acids shown below.

Amines useful in the synthesis of compounds described herein areexcmplified by the compounds shown following.

Synthesis of isoxazole containing compounds useful in the compositionsand methods described herein can follow synthetic procedures known inthe art and/or described herein. An exemplary synthetic pathway isprovided in Scheme 2 following.

With reference to Scheme 2, phenylacetylene, optionally substituted withsubstituent R′, can react with a nitroacetic acid ester to provide theisoxazole. This [3+2] cycloaddition reaction is catalyzed by base (e.g.,DBU) to form the nitronate which then undergoes cycloaddition. Removalof the esterified substitutent R is conveniently catalyzed by LiOH andTHF in water to afford the phenylisoxazole acid. Subsequence reaction ofthe phenylisoxazole acid with amine, in the presence of suitablecatalysts (e.g., EDC, HoBT and DIPEA) can afford isoxazoles useful inthe compositions and methods described herein.

Example 1.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1)

4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated withm-toluidine (729 mg, 6.8 mmol) using method A to give4-(3,4-dihydroquinolin-1 (2H)-ylsulfonyl)benzoic acid as an off whitesolid. Yield: 310 mg (43%). ¹H-NMR: 8.04 (d, J=8.7 Hz, 2H), 7.70 (d,J=8.7 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.22-7.15 (m, 1H), 7.12-7.04 (m,2H), 3.81-3.75 (m, 2H), 2.40 (t, 6.8 Hz, 2H), 1.62-1.53 (m, 2H).

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (400 mg, 1.26mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (290 mg, 1.64mmol) using method C. The residue was purified using flashchromatography eluting with 50-100% EtOAc in hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as anoff-white solid. Yield: 235 mg (39%). ¹H-NMR: 8.63-8.60 (m, 1H), 8.21(d, J=8.5 Hz, 2H), 8.00 (d, J=8.0 Hz, 7.93-7.88 (m, 2H), 7.76 (d, J=8.5Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H),7.24-7.19 (m, 1H), 7.14-7.08 (m, 2H), 3.84-3.79 (m, 2H), 2.93 (t, J=8.5Hz, 2H). 2.45 (t, J=6.5 Hz, 2H), 1.66-1.58 (m, 2H).

Example 2.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-p-tolylthiazol-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 4-p-tolylthiazol-2-amine (50 mg, 0.26 mmol) usingmethod B. The residue was purified using flash chromatography elutingwith 0-30% EtOAc in hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-p-tolylthiazol-2-yl)benzamide as a yellow solid.Yield: 18 mg (14%). ¹H-NMR: 8.21 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.0 Hz,2H), 7.75 (d, J=8.5 Hz, 2H), 7.65 (s, 1H), 7.61 (d, J=8.0 Hz, 1H),7.27-7.19 (m, 3H), 7.14-7.08 (m, 2H), 3.84-3.80 (m, 2H), 2.45 (t, J=7.0Hz, 2H), 1.66-1.59 (m, 2H).

Example 3.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-phenylthiazol-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 4-phenylthiazol-2-amine (43 mg, 0.24 mmol) usingmethod B. The residue was purified using flash chromatography elutingwith 0-40% EtOAc in hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-phenylthiazol-2-yl)benzamideas a white solid. Yield: 43 mg, (37%). ¹H-NMR: 8.21 (d, J=8.5 Hz, 2H),7.95 (d, J=8.0 Hz, 2H), 7.78-7.73 (m, 3H), 7.62 (d, J=8.5 Hz, 1H),7.47-7.42 (t, J=7.5 Hz, 2H), 7.36-7.32 (m, 1H), 7.24-7.08 (m, 3H),3.84-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.59 (m, 2H).

Example 4.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 6-methylbenzo[d]thiazol-2-amine (43 mg, 0.26mmol) using method B. The residue was purified using flashchromatography eluting with 0-30% EtOAc in hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide as a whitesolid. Yield: 34 mg (28%). ¹H-NMR: 8.21 (d, J=8.5 Hz, 2H), 7.81 (s, 1H),7.77 (d, J=8.5 Hz, 2H), 7.68 (br s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.29(dd, J=8.0, 1.0 Hz, 1H), 7.24-7.19 (m, 1H), 7.13-7.06 (m, 2H), 3.84-3.80(m, 2H), 2.47-2.41 (m, 5H), 1.66-1.59 (m, 2H).

Example 5.N-(4-(4-acetamidophenyl)thiazol-2-yl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with N-(4-(2-aminothiazol-4-yl)phenyl)acetamide (57mg, 0.24 mmol) using method B. The residue was purified using flashchromatography eluting with 0-60% EtOAc in hexanes to giveN-(4-(4-acetamidophenyl)thiazol-2-yl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as a white solid. Yield: 28 mg (22%). ¹H-NMR:10.02 (s, 1H), 8.20 (d, J=8.5 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.75 (d,J=8.5 Hz, 2H), 7.67-7.58 (m, 4H), 7.24-7.18 (m, 1H), 7.14-7.08 (m, 2H),3.84-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.06 (s, 3H), 1.66-1.59 (m,2H).

Example 6.3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (2)

3-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with1,2,3,4-tetrahydroquinoline (906 mg, 6.80 mmol) using method A to give3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid as an off whitesolid. Yield: 318 mg (44%). ¹H-NMR: 8.17 (d, J=8.0 Hz, 1H), 8.06-8.04(m, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.61 (d, J=8.0Hz, 1H), 7.24-7.18 (m, 1H), 7.15-7.05 (m, 2H), 3.80-3.76 (m, 2H), 2.40(t, J=6.5 Hz, 2H), 1.61-1.54 (m, 2H).

3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (2) (100 mg, 0.32mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (47 mg, 0.26mmol) using method C. The residue was purified using flashchromatography eluting with 75-100% EtOAc in hexanes. The resultingsolid was triturated with diethyl ether to give3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas an off white solid. Yield: 36 mg (29%). ¹H-NMR: 8.65-8.61 (m, 1H),8.50 (s, 1H), 8.42-8.35 (m, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.95-7.88 (m,2H), 7.75-7.68 (m, 2H), 7.64 (d, J=8.5 Hz, 1H) 7.39-7.32 (m, 1H),7.25-7.18 (m, 1H), 7.12-7.05 (m, 2H), 3.88-3.81 (m, 2H), 2.44 (t, J=7.0Hz, 2H), 1.68-1.60 (m, 2H).

Example 7.3-(indolin-1-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

3-(indolin-1-ylsulfonyl)benzoic acid (3)

4-(chlorosulfonyl)benzoic acid (2.0 g, 9.1 mmol) was treated with wastreated with indoline (2.7 g, 22.7 mmol) using method A to give3-(indolin-1-ylsulfonyl)benzoic acid as a light purple solid. Yield: 1.6g (58%). ¹H-NMR: 8.23 (t, J=1.5 Hz, 1H), 8.19 (dt, J=8.0, 1.5, 1.5 Hz,1H), 8.04 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 7.49(d, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 6.99(dt, J=7.5, 7.5, 1.0 Hz, 1H), 3.92 (t, J=8.5 Hz, 2H), 2.90 (t, J=8.5 Hz,2H)

3-(indolin-1-ylsulfonyl)benzoic acid (3) (100 mg, 0.33 mmol) was treatedwith 4-(pyridin-2-yl)thiazol-2-amine (49 mg, 0.28 mmol) using method C.The residue was purified using flash chromatography eluting with 75-100%EtOAc in hexanes. The resulting solid was triturated with diethyl etherto give3-(indolin-1-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as awhite solid. Yield: 17 mg (13%). ¹H-NMR: 8.65-8.61 (m, 1H), 8.60-8.58(m, 1H), 8.38 (dt, J=8.0, 1.0, 1.0 Hz, 1H), 8.05-7.99 (m, 2H), 7.95-7.88(m, 2H), 7.74 (t, J=8.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.38-7.33 (m,1H), 7.22 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H) 6.99 (dt, J=7.5,7.5, 1.0 Hz, 1H), 4.03 (t, J=8.5 Hz, 2H), 2.93 (t, J=8.5 Hz, 2H).

Example 8.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-methoxyphenyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 3-methoxyaniline (30 mg, 0.24 mmol) using methodB. The residue was purified using flash chromatography eluting with0-30% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-methoxyphenyl)benzamide as a white solid. Yield:13 mg (13%). ¹H-NMR: 10.41 (s, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.74 (d,J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.43-7.41 (m, 1H), 7.34 (d, J=8.5Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.24-7.18 (m, 1H), 7.12-7.08 (m, 2H),6.70 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 3.85-3.79 (m, 2H), 2.45 (t, J=7.0Hz, 2H), 1.67-1.59 (m, 2H).

Example 9.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-(1-hydroxyethyl)phenyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 1-(3-aminophenyl)ethanol (33 mg, 0.24 mmol) usingmethod B. The residue was purified using flash chromatography elutingwith 0-40% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-(1-hydroxyethyl)phenyl)benzamideas a white solid. Yield: 38 mg (36%). ¹H-NMR: 10.42 (br s, 1H), 8.06 (d,J=8.5 Hz, 2H), 7.77-7.71 (m, 3H), 7.63 (d, J=8.0 Hz, 2H), 7.28 (t, J=8.0Hz, 1H), 7.24-7.18 (m, 1H), 7.12-7.06 (m, 2H), 5.19 (d, J=4.0 Hz, 1H),4.74-4.66 (m, 1H), 3.84-3.80 (m, 2H), 2.46 (t, J=7.5 Hz, 2H), 1.67-1.59(m, 2H), 1.31 (d, J=6.5 Hz, 3H).

Example 10.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(pyridin-4-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 4-aminopyridine (25 mg, 0.26 mmol) using methodC. The residue was purified using flash chromatography eluting with10-50 EtOAc in dichloromethane. The resulting solid was triturated withdichloromethane/hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(pyridin-4-yl)benzamide as awhite solid. Yield: 41 mg (40%). ¹H-NMR: 10.79 (s, 1H), 8.50-8.47 (m,2H), 8.06 (d, J=8.5 Hz, 2H), 7.79-7.73 (m, 4H), 7.63 (d, J=8.0 Hz, 1H),7.23-7.08 (m, 3H) 3.85-3.81 (m, 2H), 2.45 (t, J=7.0, 2H), 1.67-1.59 (m,2H).

Example 11.4-(N-(4-fluorophenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(N-(4-fluorophenyl)-N-methylsulfamoyl)benzoic acid (4)

4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with4-fluoro-N-methylaniline (851 mg, 6.80 mmol) using method A to give4-(N-(4-fluorophenyl)-N-methylsulfamoyl)benzoic acid as a white solid.Yield: 534 mg (76%). ¹H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz,2H), 7.23-7.11 (m, 4H), 3.15 (s, 3H).

4-(N-(4-fluorophenyl)-N-methylsulfamoyl)benzoic acid (4) (100 mg, 0.32mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (48 mg, 0.27mmol) using method C. The residue was purified using flashchromatography eluting with EtOAc. The resulting solid was trituratedwith diethyl ether to give4-(N-(4-fluorophenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas a yellow solid. Yield: 34 mg (27%). ¹H-NMR: 8.61 (d, J=4.5 Hz, 1H),8.29 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.5 Hz, 1H), 7.93-7.83 (m, 2H), 7.65(d, J=8.5 Hz, 2H), 7.36-7.31 (m, 1H), 7.24-7.12 (m, 4H), 3.17 (s, 3H).

Example 12.4-(N-(4-chlorophenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(N-(4-chlorophenyl)-N-methylsulfamoyl)benzoic acid (5)

4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with4-chloro-N-methylaniline (963 mg, 6.80 mmol) using method A to give4-(N-(4-chlorophenyl)-N-methylsulfamoyl)benzoic acid as a white solid.Yield: 406 mg (55%). ¹H-NMR: 8.11 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz,2H), 7.42 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 3.15 (s, 3H).

4-(N-(4-chlorophenyl)-N-methylsulfamoyl)benzoic acid (5) (100 mg, 0.31mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (45 mg, 0.26mmol) using method C. The residue was purified using flashchromatography eluting with EtOAc. The resulting solid was trituratedwith diethyl ether to give4-(N-(4-chlorophenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas a yellow solid. Yield: 18 mg (15%). ¹H-NMR: 8.64-8.61 (m, 1H), 8.29(d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.95-7.87 (m, 2H), 7.68 (d,J=8.5 Hz, 2H), 7.46-7.41 (m, 2H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H),7.19-7.14 (m, 2H), 3.19 (s, 3H).

Example 13.4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid (6)

4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated withN-methyl-4-(trifluoromethyl)aniline (1191 mg, 6.80 mmol) using method Ato give 4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl)benzoic acidas a white solid. Yield: 385 mg (47%). ¹H-NMR: 8.11 (d, J=8.5 Hz, 2H),7.74 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H),3.21 (s, 3H).

4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid (6) (100mg, 0.28 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (41 mg,0.23 mmol) using method C. The residue was purified using flashchromatography eluting with EtOAc. The resulting solid was trituratedwith diethyl ether to give4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas a yellow solid. Yield: 42 mg (35%). ¹H-NMR: 8.60 (d, J=4.0 Hz, 1H),8.28 (d, J=8.5 Hz, 2H), 8.02 (d, J=7.5 Hz, 1H), 7.89 (dt, J=7.5, 7.5,1.5 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.5 Hz,2H), 7.41 (d, J=8.5 Hz, 2H), 7.33 (dd, J=7.0, 5.0 Hz, 1H), 3.25 (s, 1H).

Example 14.4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7)

4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with4-methoxy-N-methylaniline (933 mg, 6.80 mmol) using method A to give4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid as a yellow solid.Yield: 617 mg (85%). ¹H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz,2H), 6.98 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 3.74 (s, 3H), 3.13(s, 3H).

4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (46 mg, 0.26mmol) using method C. The residue was purified using flashchromatography eluting with EtOAc. The resulting solid was trituratedwith diethyl ether to give4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas a yellow solid. Yield: 39 mg (31%). ¹H-NMR: 8.64-8.61 (m, 1H), 8.28(d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 2H), 7.67 (d,J=8.5 Hz, 2H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.03-6.99 (m, 2H),6.91-6.88 (m, 2H), 3.75, s, 3H), 3.16 (s, 3H).

Example 15.4-(5-chloroindolin-1-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(5-chloroindolin-1-ylsulfonyl)benzoic acid (8)

3-(chlorosulfonyl)benzoic acid (1.0 g, 4.53 mmol) was treated with5-chloroindoline (2.08 g, 13.60 mmol) using method A to give3-(5-chloroindolin-1-ylsulfonyl)benzoic acid as an off white solid.Yield: 720 mg (47%). ¹H-NMR: 8.09 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.5 Hz,2H), 7.48-7.43 (m, 1H), 7.27-7.23 (m, 2H), 3.97 (t, J=8.5 Hz, 2H) 2.91(t, J=8.5 Hz, 2H).

3-(5-chloroindolin-1-ylsulfonyl)benzoic acid (8) (100 mg, 0.30 mmol) wastreated with 4-(pyridin-2-yl)thiazol-2-amine (44 mg, 0.25 mmol) in DMF(2 mL) using method C. The residue was purified using flashchromatography eluting with EtOAc. The resulting solid was trituratedwith diethyl ether to give4-(5-chloroindolin-1-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas an off white solid. Yield: 53 mg (43%). ¹H-NMR: 8.63-8.59 (m, 1H),8.25 (d, J=8.5 Hz, 2H), 8.02-7.86 (m, 5H), 7.49 (d, J=8.5 Hz, 1H), 7.34(ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.29-7.24 (m, 2H), 4.00 (t, J=8.5 Hz,2H), 2.94 (t, J=8.5 Hz, 2H)

Example 16.4-(5-chloroindolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide

3-(5-chloroindolin-1-ylsulfonyl)benzoic acid (8) (100 mg, 0.30 mmol) wastreated with 4-(pyridin-2-yl)thiazol-2-amine (44 mg, 0.25 mmol) usingmethod C. The residue was purified using flash chromatography elutingwith 0-50% EtOAc in hexanes. The resulting solid was triturated withdiethyl ether to give4-(5-chloroindolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamideas an off white solid. Yield: 29 mg (24%). ¹H-NMR: 8.24 (d, J=8.5 Hz,2H), 7.98 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.5 Hz, 1H), 7.61 (d, J=2.5 Hz,1H), 7.49 (d, J=8.5 Hz, 1H), 7.29-7.24 (m, 2H), 7.06 (dd, J=8.5, 2.5 Hz,1H), 4.04-3.96 (m, 2H), 3.82 (s, 3H), 2.94 (t, J=8.5 Hz, 2H).

Example 17.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-2-fluoro-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-2-fluorobenzoic acid (9) (160mg, 0.48 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (70 mg,0.40 mmol) using method C. The residue was purified using flashchromatography eluting with EtOAc. The resulting solid was trituratedwith diethyl ether to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-2-fluoro-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide asan off white solid. Yield: 38 mg (19%). ¹H-NMR: 8.63-8.60 (m, 1H),7.98-7.85 (m, 4H), 7.61 (d, J=8.5 Hz, 2H), 7.52 (dd, J=8.5, 2.0 Hz, 1H),7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.26-7.20 (m, 1H), 7.15-7.12 (m,2H), 3.87-3.82 (m, 2H), 2.51-2.47 (m, 2H), 1.71-1.63 (m, 2H).

Example 18.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-(4-fluorophenyl)-1H-pyrazol-5-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 3-(4-fluorophenyl)-1H-pyrazol-5-amine (43 mg,0.24 mmol) using method B. The residue was purified using flashchromatography eluting with 0-8% MeOH in EtOAc. The resulting solid wastriturated with dichloromethane/hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-(4-fluorophenyl)-1H-pyrazol-5-yl)benzamideas an off white solid. Yield: 36 mg (31%). ¹H-NMR: 11.11 (s, 1H), 8.10(d, J=8.5 Hz, 2H), 7.80 (dd, J=8.5, 5.5 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H),7.62 (d, J=8.5 Hz, 1H), 7.33-7.08 (m, 5H), 7.01 (br s, 1H), 3.83-3.79(m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.58 (m, 2H).

Example 19.4-(N-(4-methoxyphenyl)sulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(N-(4-methoxyphenyl)sulfamoyl)benzoic acid (10)

4-(chlorosulfonyl)benzoic acid (573 mg, 2.60 mmol) was treated with4-methoxyaniline (800 mg, 6.5 mmol) using method A to give4-(N-(4-methoxyphenyl)sulfamoyl)benzoic acid as an off white solid.Yield: 528 mg (66%). ¹H-NMR: 10.05 (s, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.80(d, J=8.5 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 3.67(s, 3H).

4-(N-(4-methoxyphenyl)sulfamoyl)benzoic acid (10) (104 mg, 0.34 mmol)was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol)using method C. The residue was purified using flash chromatographyeluting with EtOAc. The resulting solid was triturated with diethylether to give4-(N-(4-methoxyphenyl)sulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas a yellow solid. Yield: 29 mg (25%). ¹H-NMR: 10.08 (s, 1H), 8.63-8.60(m, 1H), 8.21 (d, J=8.5 Hz, 2H), 8.04-7.87 (m, 3H), 7.82 (d, J=8.5 Hz,2H), 7.34 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.01-6.90 (m, 3H), 6.82 (d,J=9.0 Hz, 2H), 3.66 (s, 3H).

Example 20.4-(N-(3-chlorophenyl)sulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(N-(3-chlorophenyl)sulfamoyl)benzoic acid (11)

4-(chlorosulfonyl)benzoic acid (22) (553 mg, 2.60 mmol) was treated with3-chloroaniline (800 mg, 6.3 mmol) using method A to give4-(N-(3-chlorophenyl)sulfamoyl)benzoic acid as an off white solid.Yield: 382 mg (49%). ¹H-NMR: 10.73 (s, 1H), 8.09 (d, J=8.5 Hz, 2H), 7.88(d, J=8.5 Hz, 2H), 7.27 (t, J=8.5 Hz, 1H), 7.13-7.04 (m, 3H).

4-(N-(3-chlorophenyl)sulfamoyl)benzoic acid (11) (106 mg, 0.34 mmol) wastreated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) usingmethod C. The residue was purified using flash chromatography elutingwith 50-100% EtOAc in hexanes. The resulting solid was triturated withdiethyl ether to give4-(N-(3-chlorophenyl)sulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas a yellow solid. Yield: 49 mg (37%). ¹H-NMR: 10.77 (s, 1H), 8.63-8.61(m, 1H), 8.25 (d, J=8.5 Hz, 2H), 8.00 (d, J=8.0 Hz, 1H), 7.95-7.88 (m,4H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.15(t, J=2 Hz, 1H), 7.13-7.08 (m, 2H), 3.32 (s, 3H).

Example 21.4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (12)

4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with3-methoxy-N-methylaniline (933 mg, 6.8 mmol) using method A to give4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)benzoic acid as an off whitesolid. Yield: 398 mg (55%). ¹H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.66 (d,J=8.5 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 6.88 (ddd, J=8.5, 2.5, 1.0 Hz,1H), 6.67-6.64 (m, 2H), 3.69 (s, 3H), 3.16 (s, 3H).

4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (12) (100 mg, 0.31mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28mmol) using method C. The residue was purified using flashchromatography eluting with 50-100% EtOAc in hexanes. The resultingsolid was triturated with diethyl ether to give4-(N-(3-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas a yellow solid. Yield: 56 mg (41%). ¹H-NMR: 8.64-8.61 (m, 1H), 8.28(d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 3H), 7.71 (d,J=8.5 Hz, 2H), 7.36 (ddd, 7.5, 5.0, 1.0 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H),6.92-6.88 (m, 1H), 6.71-6.67 (m, 2H), 3.70 (s, 3H), 3.20 (s, 3H).

Example 22.4-(N-(2-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(N-(2-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (13)

4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with2-methoxy-N-methylaniline (933 mg, 6.8 mmol) using method A to give4-(N-(2-methoxyphenyl)-N-methylsulfamoyl)benzoic acid as an off whitesolid. Yield: 515 mg (71%). ¹H-NMR: 8.11 (d, J=8.5 Hz, 2H), 7.73 (d,J=8.5 Hz, 2H), 7.33 (ddd, J=8.5, 7.5, 1.5 Hz, 1H), 7.17 (dd, J=7.5, 1.5Hz, 1H), 7.00-6.92 (m, 2H), 3.33 (s, 3H), 3.14 (s, 3H).

4-(N-(2-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (13) (109 mg, 0.34mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28mmol) using method C. The residue was purified using flashchromatography eluting with 50-100% EtOAc in hexanes. The resultingsolid was triturated with diethyl ether to give4-(N-(2-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas an off white solid. Yield: 46 mg (34%). ¹H-NMR: 8.65-8.62 (m, 1H),8.27 (d, J=8.5 Hz, 2H), 8.03 (d, J=7.5 Hz, 1H), 7.95-7.89 (m, 2H), 7.77(d, J=8.5 Hz, 2H), 7.38-7.32 (m, 2H), 7.22 (dd, J=7.5, 1.5 Hz, 1H),7.01-6.94 (m, 2H), 3.34 (s, 3H), 3.18 (s, 3H).

Example 23.N-(4-(pyridin-2-yl)thiazol-2-yl)-4-(N-m-tolylsulfamoyl)benzamide

4-(N-m-tolylsulfamoyl)benzoic acid (14)

4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated withm-toluidine (729 mg, 6.8 mmol) using method A to give4-(N-m-tolylsulfamoyl)benzoic acid as an off white solid. Yield: 463 mg(70%). ¹H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.22 (t,J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.85 (d, J=8.0 Hz,1H), 3.14 (s, 3H), 2.26 (s, 3H).

4-(N-m-tolylsulfamoyl)benzoic acid (14) (99 mg, 0.34 mmol) was treatedwith 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C.The residue was purified using flash chromatography eluting with 75-100%EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to giveN-(4-(pyridin-2-yl)thiazol-2-yl)-4-(N-m-tolylsulfamoyl)benzamide as anoff white solid. Yield: 24 mg (19%). ¹H-NMR: 8.64-8.62 (m, 1H), 8.28 (d,J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.95-7.89 (m, 2H), 7.69 (d, J=8.5Hz, 2H), 7.36 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H),7.13 (d, J=7.5 Hz, 1H), 6.98-6.96 (m, 1H), 6.88 (d, J=8.0 Hz, 1H), 3.18(s, 3H).

Example 24.4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide

4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31mmol) was treated with 6-methylbenzo[d]thiazol-2-amine (43 mg, 0.26mmol) using method C. The residue was purified using flashchromatography eluting with 0-30% EtOAc in hexanes. The resulting solidwas triturated with dichloromethane/hexanes to give4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamideas an off white solid. Yield: 57 mg (47%). ¹H-NMR: 8.28 (d, J=8.5 Hz,2H), 7.83 (s, 1H), 7.74-7.63 (m, 3H), 7.30 (dd, J=8.0, 1.5 Hz, 1H), 7.00(d, J=8.5 Hz, 1H), 6.90 (d, J=8.5 Hz, 2H), 3.75 (s, 3H), 3.16 (s, 3H),2.44 (s, 3H).

Example 25.N-(6-methoxybenzo[d]thiazol-2-yl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide

4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31mmol) was treated with 6-methoxybenzo[d]thiazol-2-amine (47 mg, 0.26mmol) using method C. The residue was purified using flashchromatography eluting with 0-40% EtOAc in hexanes. The resulting solidwas triturated with dichloromethane/hexanes to giveN-(6-methoxybenzo[d]thiazol-2-yl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamideas a yellow solid. Yield: 26 mg (21%). ¹H-NMR: 8.28 (d, J=8.5 Hz, 2H),7.74-7.61 (m, 4H), 7.08 (dd, J=9.0, 2.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 2H),6.91-6.88 (m, 2H), 3.83 (s, 3H), 3.74 (s, 3H), 3.16 (s, 3H).

Example 26.N-(4-(4-acetamidophenyl)thiazol-2-yl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide

4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31mmol) was treated with N-(4-(2-aminothiazol-4-yl)phenyl)acetamide (61mg, 0.26 mmol) using method C. The residue was purified using flashchromatography eluting with 30-90% EtOAc in hexanes. The resulting solidwas triturated with dichloromethane/hexanes to giveN-(4-(4-acetamidophenyl)thiazol-2-yl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamideas a yellow solid. Yield: 68 mg (49%). ¹H-NMR: 10.03 (s, 1H), 8.27 (d,J=9.0 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.68-7.63 (m, 4H), 7.60 (s, 1H),7.01 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 3.75 (s, 3H), 3.16 (s,3H).

Example 27.4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(pyridin-4-yl)benzamide

4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31mmol) was treated with 4-aminopyridine (24 mg, 0.26 mmol) using methodC. The residue was purified using flash chromatography eluting with0-70% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to give4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(pyridin-4-yl)benzamide asan off white solid. Yield: 67 mg (65%). ¹H-NMR: 10.82 (s, 1H), 8.51 (d,J=6.0 Hz, 2H), 8.12 (d, J=8.5 Hz, 2H), 7.78 (d, J=6.0 Hz, 2H), 7.69 (d,J=8.5 Hz, 2H), 7.01 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 3.75 (s,3H), 3.15 (s, 3H).

Example 28.N-(3-(1-hydroxyethyl)phenyl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide

4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31mmol) was treated with 1-(3-aminophenyl)ethanol (36 mg, 0.26 mmol) usingmethod C. The residue was purified using flash chromatography elutingwith 0-40% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to giveN-(3-(1-hydroxyethyl)phenyl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide as an off white solid. Yield: 52 mg (46%). ¹H-NMR:10.45 (s, 1H), 8.12 (d, J=8.5 Hz, 2H), 7.75-7.74 (m, 1H), 7.68-7.64 (m,3H), 7.30 (t, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz,2H), 6.90 (d, J=8.0 Hz, 2H), 5.19 (d, J=4.5 Hz, 1H), 4.75-4.68 (m, 1H),3.75 (s, 3H), 3.15 (s, 3H), 1.33 (d, J=6.5 Hz, 3H).

Example 29.N-(4-(4-acetamidophenyl)thiazol-2-yl)-3-(indolin-1-ylsulfonyl)benzamide

3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and amine(128 mg, 0.55 mmol) using method C. The residue was purified using flashchromatography eluting with 30-90% EtOAc in hexanes. The resulting solidwas triturated with dichloromethane/hexanes to giveN-(4-(4-acetamidophenyl)thiazol-2-yl)-3-(indolin-1-ylsulfonyl)benzamideas an off white solid. Yield: 78 mg (27%). ¹H-NMR: 10.02 (s, 1H), 8.58(s, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.88 (d, J=8.5Hz, 2H), 7.74 (t, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.60 (s, 1H),7.53 (d, J=8.0 Hz, 1H), 7.22 t, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H),6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.03 (t, J=8.5 Hz, 1H), 2.93 (t,J=8.5 Hz, 1H), 2.06 (s, 3H).

Example 30.N-(3-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(indolin-1-ylsulfonyl)benzamide

3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and amine(97 mg, 0.55 mmol) using method C. The residue was purified using flashchromatography eluting with 0-30% EtOAc in hexanes. The resulting solidwas triturated with dichloromethane/hexanes to giveN-(3-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(indolin-1-ylsulfonyl)benzamideas a yellow solid. Yield: 49 mg (19%). ¹H-NMR: 8.58 (t, J=2.0 Hz, 1H),8.31 (ddd, J=8.0, 1.0, 1.0 Hz, 1H), 8.02 (ddd, J=8.0, 2.0, 1.0 Hz, 1H),7.79-7.71 (m, 3H), 7.53-7.47 (m, 3H), 7.20-7.14 (m, 1H), 6.99 (dt,J=7.5, 7.5, 1.0 Hz, 1H), 6.93 (s, 2H), 5.92 (s, 1H), 3.97 (s, 3H), 2.93(t, J=8.5 Hz, 2H).

Example 31.4-(N-(4-(benzyloxy)phenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(N-(4-(benzyloxy)phenyl)-N-methylsulfamoyl)benzoic acid (15)

4-(chlorosulfonyl)benzoic acid (1.0 g, 4.53 mmol) was treated with4-(benzyloxy)-N-methylaniline (1.45 g, 6.8 mmol) and DIPEA (0.59 g, 4.53mmol) using method A to give4-(N-(4-(benzyloxy)phenyl)-N-methylsulfamoyl)benzoic acid as an offwhite solid. Yield: 716 mg (40%). ¹H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.62(d, J=8.5 Hz, 2H), 7.46-7.30 (m, 5H), 7.01-6.94 (m, 4H), 5.08 (s, 2H),3.13 (s, 3H).

4-(N-(4-(benzyloxy)phenyl)sulfamoyl)benzoic acid (15) (493 mg, 1.24mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (200 mg, 1.13mmol) using method C. The residue was purified using flashchromatography eluting with 0-8% MeOH in dichloromethane. The resultingsolid was triturated with diethyl ether to give4-(N-(4-(benzyloxy)phenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas an off white solid. Yield: 289 mg (46%). ¹H-NMR: 8.62 (d, J=5.0 Hz,1H), 8.29 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 2H),7.67 (d, J=8.5 Hz, 2H), 7.46-7.31 (m, 6H), 7.04-6.96 (m, 4H), 5.10 (s,2H), 3.16 (s, 3H).

Example 32.4-(N-methyl-N-phenylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(N-methyl-N-phenylsulfamoyl)benzoic acid (16)

4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated withN-methylaniline (729 mg, 6.8 mmol) using method A to give4-(N-methyl-N-phenylsulfamoyl)benzoic acid as an off-white solid. Yield:374 mg (57%). ¹H-NMR: 8.09 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H),7.38-7.28 (m, 3H), 7.13-7.08 (m, 2H), 3.17 (s, 3H).

4-(N-methyl-N-phenylsulfamoyl)benzoic acid (16) (100 mg, 0.31 mmol) wastreated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) usingmethod C. The residue was purified using flash chromatography elutingwith 50-100% EtOAc in hexanes. The resulting solid was triturated withdiethyl ether to give4-(N-methyl-N-phenylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamideas an orange solid. Yield: 31 mg (24%). ¹H-NMR: 8.63-8.61 (m, 1H), 8.28(d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 2H), 7.68 (d,J=8.5 Hz, 2H), 7.40-7.30 (m, 4H), 7.13 (d, J=7.0 Hz, 2H), 3.20 (s, 3H).

Example 33.4-(6-methoxy-3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(6-methoxy-3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (17)

4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with6-methoxy-1,2,3,4-tetrahydroquinoline (1.0 g, 6.13 mmol) using method Ato give 4-(6-methoxy-3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acidas an off-white solid. Yield: 358 mg (46%). ¹H-NMR: 8.04 (d, J=8.5 Hz,2H), 7.64 (d, J=8.5 Hz, 2H), 7.52 (d, J=9.0 Hz, 1H), 6.81 (dd, J=9.0,3.0 Hz, 1H), 6.65 (d, J=3.0 Hz, 1H), 3.75-3.70 (m, 5H), 2.29 (t, J=7.0Hz, 2H), 1.53-1.45 (m, 2H).

4-(6-methoxy-3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (17) (118mg, 0.34 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg,0.28 mmol) using method C. The residue was purified using flashchromatography eluting with 50-100% EtOAc in hexanes. The resultingsolid was triturated with diethyl ether to give4-(6-methoxy-3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as anoff-white solid. Yield: 56 mg (39%). ¹H-NMR: 8.64-8.61 (m, 1H), 8.21 (d,J=8.5 Hz, 2H), 8.01 (d, J=7.5 Hz, 1H), 7.94-7.88 (m, 2H), 7.69 (d, J=8.5Hz, 2H), 7.58-7.45 (m, 2H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 6.83(dd, J=9.0, 3.0 Hz, 1H), 6.67 (d, J=3.0 Hz, 1H), 3.79-3.70 (m, 5H), 2.33(t, J=7.0, 2H), 1.57-1.48 (m, 2H).

Example 34.N-(benzo[d]thiazol-2-yl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with benzo[d]thiazol-2-amine (39 mg, 0.26 mmol) usingmethod B. The residue was purified using flash chromatography elutingwith 0-20% EtOAc in hexanes to giveN-(benzo[d]thiazol-2-yl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamideas an off-white solid. Yield: 29 mg (25%). ¹H-NMR: 8.22 (d, J=8.5 Hz,2H), 8.02 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.0 Hz,1H), 7.50-7.45 (m, 1H), 7.37-7.32 (m, 1H), 7.24-7.19 (m, 1H), 7.14-7.08(m, 2H), 3.84-3.80 (m, 2H), 2.44 (t, J=7.0 Hz, 2H), 1.66-1.58 (m, 2H).

Example 35.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-methylbenzo[d]thiazol-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 4-methylbenzo[d]thiazol-2-amine (44 mg, 0.24mmol) using method B. The residue was purified using flashchromatography eluting with 0-30% EtOAc in hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-methylbenzo[d]thiazol-2-yl)benzamide as a whitesolid. Yield: 24 mg (21%). ¹H-NMR: 8.22 (d, J=8.5 Hz, 2H), 7.84 (d,J=8.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 h, 1H), 7.31-7.08(m, 5H), 3.85-3.79 (m, 2H), 2.62 (s, 3H), 2.45 (t, J=7.0 Hz, 2H),1.66-1.58 (m, 2H).

Example 36.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-fluorobenzo[d]thiazol-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 6-fluorobenzo[d]thiazol-2-amine (41 mg, 0.24mmol) using method B. The residue was purified using flashchromatography eluting with 0-40% EtOAc in hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-fluorobenzo[d]thiazol-2-yl)benzamide as anoff-white solid. Yield: 22 mg (19%). ¹H-NMR: 8.22 (d, J=8.5 Hz, 2H),7.94 (dd, J=8.5, 2.5 Hz, 1H), 7.84-7.75 (m, 3H), 7.61 (d, J=8.5 Hz, 2H),7.33 (dt, J=9.0, 3.0 Hz, 1H), 7.24-7.19 (m, 1H), 7.14-7.08 (m, 2H),3.84-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.58 (m, 2H).

Example 37.3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide

3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (18) (100 mg, 0.32mmol) was treated with 6-methoxybenzo[d]thiazol-2-amine (47 mg, 0.26mmol) using method C. The residue was purified using flashchromatography eluting with 0-30% EtOAc in hexanes. The resulting solidwas triturated with dichloromethane/hexanes to give3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamideas an off-white solid. Yield: 32 mg (25%). ¹H-NMR: 8.48 (s, 1H),8.40-8.35 (m, 1H), 7.77-7.59 (m, 5H), 7.24-7.18 (m, 1H) 7.11-7.05 (m,3H), 3.87-3.81 (m, 2H), 2.44 (t, J=6.5 Hz, 2H), 1.68-1.59 (m, 2H).

Example 38.N-(3-cyanophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 3-aminobenzonitrile (29 mg, 0.24 mmol) usingmethod B. The residue was purified using flash chromatography elutingwith 0-30% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to giveN-(3-cyanophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as awhite solid. Yield: 12 mg (12%). ¹H-NMR: 10.76 (s, 1H), 8.23-8.20 (m,1H), 8.07 (d, J=8.5 Hz, 2H), 8.03-7.98 (m, 1H), 7.77 (d, J=8.5 Hz, 2H),7.63 (d, J=8.5 Hz, 1H), 7.61-7.58 (m, 2H), 7.23-7.18 (m, 1H), 7.11-7.07(m, 2H), 3.85-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.68-1.59 (m, 2H).

Example 39.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-hydroxypyridin-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 2-aminopyridin-3-ol (29 mg, 0.26 mmol) usingmethod C. The residue was purified using flash chromatography elutingwith 0-60% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-hydroxypyridin-2-yl)benzamide as an off-whitesolid. Yield: 23 mg (21%). ¹H-NMR: 8.08 (d, J=8.5 Hz, 2H), 7.93 (dd,J=5.0, 1.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.31(dd, J=8.0, 1.5 Hz, 1H), 7.23-7.18 (m, 2H), 7.12-7.08 (m, 2H), 3.84-3.79(m, 2H), 2.44 (J=7.0 Hz, 2H), 1.66-1.58 (m, 2H).

Example 40.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-methylpyridin-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 6-methylpyridin-2-amine (28 mg, 0.26 mmol) usingmethod C. The residue was purified using flash chromatography elutingwith 0-30% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-methylpyridin-2-yl)benzamideas a white solid. Yield: 14 mg (13%). ¹H-NMR: 10.95 (s, 1H), 8.08 (d,J=8.5 Hz, 2H), 7.96 (d, J=8.5 Hz, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.69 (d,J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 1H), 7.24-7.18 (m, 1H), 7.12-7.07 (m,2H), 7.04 (d, J=7.5 Hz, 1H), 3.82-3.78 (m, 2H), 2.47-2.42 (m, 5H),1.65-1.57 (m, 2H).

Example 41.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(5-fluoropyridin-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 6-fluoropyridin-2-amine (29 mg, 0.26 mmol) usingmethod C. The residue was purified using flash chromatography elutingwith 0-5 EtOAc in dichloromethane. The resulting solid was trituratedwith dichloromethane/hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(5-fluoropyridin-2-yl)benzamideas an off-white solid. Yield: 16 mg (15%). ¹H-NMR: 11.15 (s, 1H), 8.41(d, J=3.5 Hz, 1H), 8.18 (dd, J=9.0, 4.0 Hz, 1H), 8.08 (d, J=8.5 Hz, 2H),7.81 ddd, J=9.0, 8.0, 3.0 Hz, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.61 (d,J=8.5 Hz, 1H), 7.23-7.08 (m, 3H), 3.83-3.78 (m, 2H), 2.45 (t, J=7.0,2H), 1.66-1.58 (m, 2H).

Example 42.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(pyridin-3-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 3-aminopyridine (25 mg, 0.26 mmol) using methodC. The residue was purified using flash chromatography eluting with10-50 EtOAc in dichloromethane. The resulting solid was triturated withdichloromethane/hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(pyridin-3-yl)benzamide as awhite solid. Yield: 48 mg (47%). ¹H-NMR: 10.66 (s, 1H), 8.89 (d, J=2.5Hz, 1H) 8.33 (dd, J=4.5, 1.5 Hz, 1H), 8.15 (ddd, J=8.0, 2.5, 1.5 Hz, 1H)8.08 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 1H),7.41 (ddd, J=8.5, 4.5, 0.5 Hz, 1H), 7.24-7.08 (m, 3H), 3.85-3.81 (m,2H), 2.45 (t, J=7.0, 2H), 1.67-1.59 (m, 2H).

Example 43.3-(indolin-1-ylsulfonyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide

3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and6-methylbenzo[d]thiazol-2-amine (90 mg, 0.55 mmol) in DMF (4 mL) wasadded DIPEA (213 mg, 1.65 mmol) and pybop (429 mg, 0.82 mmol). usingmethod C. The residue was purified using flash chromatography elutingwith 0-30% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to give3-(indolin-1-ylsulfonyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide as awhite solid. Yield: 78 mg (32%). ¹H-NMR: 8.58 (s, 1H), 8.38 (d, J=8 Hz,1H), 8.02 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.77-7.65 (m, 3H), 7.53 (d,J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 1.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H),7.16 (d, J=7.0 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.02 (t,J=8.5 Hz, 2H), 2.92 (t, J=8.5 Hz, 2H), 2.43 (s, 3H).

Example 44.3-(indolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide

3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and6-methoxybenzo[d]thiazol-2-amine (99 mg, 0.55 mmol) using method C. Theresidue was purified using flash chromatography eluting with 0-40% EtOAcin hexanes. The resulting solid was triturated withdichloromethane/hexanes to give3-(indolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide asan off-white solid. Yield: 89 mg (35%). ¹H-NMR: 8.57 (s, 1H), 8.37 (d,J=8 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.77-7.66 (m, 2H), 7.63 (d, J=2.5Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 7.16 (d, J=7.5Hz, 1H), 7.07 (dd, J=8.5, 2.5, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H),4.02 (t, J=8.5 Hz, 2H), 3.83 (s, 3H), 2.92 (t, J=8.5 Hz, 2H).

Example 45.4-(indolin-1-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide

4-(indolin-1-ylsulfonyl)benzoic acid (8) (100 mg, 0.33 mmol) was treatedwith 4-(pyridin-2-yl)thiazol-2-amine (49 mg, 0.28 mmol) using method C.The residue was purified using flash chromatography eluting with 50-100%EtOAc in hexanes to give4-(indolin-1-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as anoff-white solid. Yield: 61 mg (48%). ¹H-NMR: 8.63-8.59 (m, 1H), 8.23 (d,J=8.5 Hz, 2H), 8.02-7.95 (m, 3H), 7.93-7.87 (m, 2H), 7.51 (d, 8.5 Hz,1H), 7.37-7.32 (m, 1H), 7.26-7.15 (m, 2H), 7.01 (ddd, J=7.5, 7.5, 1.0Hz, 1H), 4.01-3.95 (t, J=8.5 Hz, 2H), 2.93 (t, J=8.5 Hz, 2H).

Example 46.4-(indolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide

4-(indolin-1-ylsulfonyl)benzoic acid (8) (100 mg, 0.33 mmol) was treatedwith 6-methoxybenzo[d]thiazol-2-amine (50 mg, 0.28 mmol) using method C.The residue was purified using flash chromatography eluting with 0-30%EtOAc in hexanes to give4-(indolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide as awhite solid. Yield: 24 mg (19%). ¹H-NMR: 8.23 (d, J=8.5 Hz, 2H), 7.98(d, J=8.5 Hz, 2H), 7.72-7.64 (m, 1H), 7.61 (d, J=3.0 Hz, 1H), 7.50 (d,J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 7.06 (dd,J=8.5, 3.0 Hz, 1H), 7.01 (dt, J=7.5, 1.0 Hz, 1H), 3.99 (t, J=8.5 Hz,2H), 2.93 (t, J=8.5 Hz, 2H)

Example 47.3-(indolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide

3-(indolin-1-ylsulfonyl)benzoic acid (3) (100 mg, 0.33 mmol) was treatedwith 6-methoxybenzo[d]thiazol-2-amine (46 mg, 0.25 mmol) using method C.The residue was purified using flash chromatography eluting with 0-30%EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to give3-(indolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide as awhite solid. Yield: 30 mg (25%). ¹H-NMR: 8.58 (s, 1H), 8.37 (d, J=8.0Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.77-7.59 (m, 3H), 7.53 (d, J=8.0 Hz,1H), 7.22 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.08 (dd, J=9.0,2.5 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.02 (t, J=8.0 Hz, 2H),2.93 (t, J=8.0 Hz, 2H).

Example 48.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(2-methoxyphenyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (20) (100 mg, 0.32mmol) was treated with 2-methoxyaniline (30 mg, 0.24 mmol) using methodB. The residue was purified using flash chromatography eluting with0-20% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(2-methoxyphenyl)benzamide as a white solid. Yield:39 mg (38%). ¹H-NMR: 9.75 (s, 1H), 8.05 (d, J=8.5 Hz, 2H), 7.73 (d,J=8.5 Hz, 2H), 7.69-7.61 (m, 2H), 7.24-7.07 (m, 5H), 6.96 (dt, J=7.5,7.5, 1.0 Hz, 1H), 3.85-3.79 (m, 2H), 2.46 (t, J=7.0 Hz, 2H), 1.67-1.59(m, 2H).

Example 49.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(2-hydroxyphenyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 2-aminophenol (27 mg, 0.24 mmol) using method B.The residue was purified using flash chromatography eluting with 0-30%EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(2-hydroxyphenyl)benzamide as an off-white solid.Yield: 23 mg (23%). ¹H-NMR: 9.72 (br s, 1H), 8.07 (d, J=8.5 Hz, 2H),7.73 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H),7.24-7.02 (m, 4H), 6.91 (dd, J=8.0, 1.0 Hz, 1H), 6.81 (dt, J=8.0, 8.0,1.0 Hz, 1H), 3.85-3.79 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.59 (m,2H).

Example 50.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-methoxyphenyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 4-methoxyaniline (30 mg, 0.24 mmol) using methodB. The residue was purified using flash chromatography eluting with0-40% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-methoxyphenyl)benzamide as a white solid. Yield:47 mg (46%). ¹H-NMR: 10.33 (s, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.73 (d,J=8.5 Hz, 2H), 7.66-7.61 (m, 3H), 7.24-7.18 (m, 1H), 7.11-7.08 (m, 2H),6.93 (d, J=9.0, 2 Hz, 2H), 3.84-3.80 (m, 2H), 2.45 (t, J=6.5 Hz, 2H),1.66-1.58 (m, 2H).

Example 51.N-(2-acetamidophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with N-(2-aminophenyl)acetamide (36 mg, 0.24 mmol)using method B. The residue was purified using flash chromatographyeluting with 0-40% EtOAc in hexanes. The resulting solid was trituratedwith dichloromethane/hexanes to giveN-(2-acetamidophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamideas an off-white solid. Yield: 26 mg (24%). ¹H-NMR: 10.01 (s, 1H), 9.60(s, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.24-7.16 (m, 3H), 7.11-7.08 (m, 2H),3.85-3.80 (m, 2H), 2.47 (d, J=7.0 Hz, 2H), 2.06 (s, 3H), 1.69-1.60 (m,2H).

Example 52.N-(3-acetamidophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with N-(3-aminophenyl)acetamide (36 mg, 0.24 mmol)using method B. The residue was purified using flash chromatographyeluting with 0-60% EtOAc in hexanes. The resulting solid was trituratedwith dichloromethane/hexanes to giveN-(3-acetamidophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamideas a white solid. Yield: 44 mg (40%). ¹H-NMR: 10.46 (s, 1H), 9.97 (s,1H), 8.08 (m, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.63(d, J=8.0 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.25(d, J=8.0 Hz, 1H), 7.23-7.18 (m, 1H), 7.11-7.08 (m, 2H), 3.84-3.80 (m,2H), 2.46 (t, J=7.0 Hz, 2H), 2.04 (s, 3H), 1.67-1.59 (m, 2H).

Example 53.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(5-methyl-4-phenylthiazol-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 5-methyl-4-phenylthiazol-2-amine (46 mg, 0.24mmol) using method B. The residue was purified using flashchromatography eluting with 0-30% EtOAc in hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(5-methyl-4-phenylthiazol-2-yl)benzamide as anoff-white solid. Yield: 54 mg (46%). ¹H-NMR: 8.19 (d, J=8.5 Hz, 2H),7.74 (d, J=8.0 Hz, 2H), 7.68 (d, J=7.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 1H)7.50-7.34 (m, 3H), 7.24-7.08 (m, 3H), 3.84-3.78 (m, 2H), 2.52 (s, 3H),2.45 (t, J=7.0 Hz, 2H), 1.66-1.57 (m, 2H).

Example 54.N-(3-chlorophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 3-chloroaniline (31 mg, 0.24 mmol) using methodB. The residue was purified using flash chromatography eluting with0-20% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to giveN-(3-chlorophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide asa white solid. Yield: 24 mg (23%). ¹H-NMR: 10.60 (s, 1H), 8.05 (d, J=8.5Hz, 2H), 7.93 (t, J=2.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.66 (ddd,J=8.5, 2.0, 1.0 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H),7.24-7.16 (m, 2H), 7.12-7.07 (m, 2H), 3.86-3.80 (m, 2H), 2.45 (t, J=7.0Hz, 2H), 1.67-1.59 (m, 2H).

Example 55.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-hydroxyphenyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 3-aminophenol (29 mg, 0.26 mmol) using method C.The residue was purified using flash chromatography eluting with 0-50EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-hydroxyphenyl)benzamide asan off-white solid. Yield: 38 mg (35%). ¹H-NMR: 8.21 (d, J=8.5 Hz, 2H),7.80 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.24-7.08 (m, 3H), 7.06(t, J=8.0 Hz, 1H), 6.48 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 6.41 (t, J=2.0Hz, 1H), 6.36 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 3.84-3.80 (m, 2H), 2.45 (t,J=7.0, 2H), 1.67-1.59 (m, 2H).

Example 56.N-(3-carbamoylphenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32mmol) was treated with 3-aminobenzamide (36 mg, 0.26 mmol) using methodC. The residue was purified using flash chromatography eluting with10-50 EtOAc in dichloromethane. The resulting solid was triturated withdichloromethane/hexanes to giveN-(3-carbamoylphenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamideas a white solid. Yield: 35 mg (31%). ¹H-NMR: 10.58 (s, 1H), 8.22-8.20(m, 1H), 8.08 (d, J=8.5 Hz, 2H), 7.95 (s, 1H), 7.92-7.88 (m, 1H), 7.75(d, J=8.5 Hz, 2H), 7.62 (t, J=8.0 Hz, 2H), 7.43 (t, J=7.5 Hz, 1H), 7.35(s, 1H), 7.24-7.08 (m, 3H), 3.84-3.80 (m, 2H), 2.46 (t, J=7.0, 2H),1.67-1.59 (m, 2H).

Example 57. 3-(indolin-1-ylsulfonyl)-N-(3-methoxyphenyl)benzamide

3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and3-methoxyaniline (68 mg, 0.55 mmol) using method C. The residue waspurified using flash chromatography eluting with 0-30% EtOAc in hexanes.The resulting solid was triturated with dichloromethane/hexanes to give3-(indolin-1-ylsulfonyl)-N-(3-methoxyphenyl)benzamide as an off-whitesolid. Yield: 94 mg (42%). ¹H-NMR: 8.34 (s, 1H), 8.22 (d, J=8.0 Hz, 1H),7.99 (d, J=8.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H),7.42 (t, J=2.0 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H),7.21 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 6.99 (dt, J=7.5, 7.5,1.0 Hz, 1H), 6.71 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 3.98 (t, J=8.5 Hz, 2H),3.32 (s, 3H), 2.92 (t, J=8.5 Hz, 2H)

Example 58. 3-(indolin-1-ylsulfonyl)-N-(pyridin-4-yl)benzamide

3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and4-aminopyridine (52 mg, 0.55 mmol) using method C. The residue waspurified using flash chromatography eluting with 30-90 EtOAc in hexanes.The resulting solid was triturated with dichloromethane/hexanes to give3-(indolin-1-ylsulfonyl)-N-(pyridin-4-yl)benzamide as an off-whitesolid. Yield: 86 mg (43%). ¹H-NMR: 10.81 (s, 1H), 8.50 (d, J=6.0 Hz,2H), 8.35 (t, J=1.5 Hz, 1H), 8.24 (dt, J=8.0, 1.0, 1.0, 1H), 8.01 (dt,J=8.0, 1.0, 1.0, 1H), 7.77-7.72 (m, 3H), 7.50 (d, J=8.0 Hz, 1H), 7.21(t, J=7.5 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz,1H), 3.98 (t, J=8.5 Hz, 2H), 2.91 (t, J=8.5 Hz, 2H).

Example 59.N-(3-(1-hydroxyethyl)phenyl)-3-(indolin-1-ylsulfonyl)benzamide

3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and1-(3-aminophenyl)ethanol (75 mg, 0.55 mmol) using method C. The residuewas purified using flash chromatography eluting with 0-50% EtOAc inhexanes. The resulting solid was triturated with dichloromethane/hexanesto give N-(3-(1-hydroxyethyl)phenyl)-3-(indolin-1-ylsulfonyl)benzamideas an off-white solid. Yield: 93 mg (40%). ¹H-NMR: 10.46 (s, 1H), 8.37(s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.74-7.69 (m,2H), 7.64 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.29 (t, J=8.0 Hz,1H), 7.21 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.09 (d, J=8.0 Hz,1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 5.19 (d, J=4.0 Hz, 1H),4.75-4.68 (m, 1H), 3.98 (t, J=8.5 Hz, 2H), 2.93 (t, J=8.5 Hz, 2H), 1.32(d, J=6.0 Hz, 3H).

Example 60.4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)thiazol-2-yl)benzamide

4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (200 mg, 0.63mmol) was treated with 6-(2-aminothiazol-4-yl)benzo[d]oxazol-2(3H)-one(198 mg, 0.55 mmol) using method C. The residue was purified using flashchromatography eluting with 0-70% EtOAc in hexanes. The resulting solidwas triturated with dichloromethane/hexanes to give4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)thiazol-2-yl)benzamideas a yellow solid. Yield: 73 mg (22%). ¹H-NMR: 8.21 (d, J=8.5 Hz, 2H),7.84-7.74 (m, 4H), 7.69 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.24-7.19 (m,1H), 7.15 (d, J=8.5 Hz, 1H), 7.13-7.07 (m, 2H), 3.85-3.78 (m, 2H), 2.45(t, J=7.0 Hz, 2H), 1.67-1.58 (m, 2H).

Example 61.N-(3-methoxyphenyl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide

4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31mmol) was treated with 3-methoxyaniline (32 mg, 0.26 mmol) using methodC. The residue was purified using flash chromatography eluting with0-30% EtOAc in hexanes. The resulting solid was triturated withdichloromethane/hexanes to giveN-(3-methoxyphenyl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamideas a white solid. Yield: 70 mg (63%). ¹H-NMR: 10.44 (s, 1H), 8.10 (d,J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.45 (t, J=2.0 Hz, 1H), 7.37 (d,J=8.0 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.90 (d,J=8.5 Hz, 2H), 6.72 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 3.76 (s, 3H), 3.75(s, 3H), 3.15 (s, 3H).

Example 62. Commercially available compounds

Compounds useful in the compositions and methods described herein mayinclude the following.

Example 63. Screening Procedures

Drug stocks and dilutions.

Compounds are prepared as 10 mM stocks for each compound in DMSO.Dilutions are prepared in a 96-well plate in DMSO. The stock dilutionsare as follows: 10 mM, 3 mM, 1 mM, 300 μM, 100 μM, 30 μM, 10 μM, 3 μM, 1μM, 300 nM, 100 nM, and 30 nM. Plates are then sealed and stored at −20C.

Screening with STF293 and SW480STF.

HEK STF293 cells are seeded at approximately 25,000-30,000 cells/well ina 96-well (100 uL volume). On the first day, Wnt3a-conditioned media(1:1) will be added along with diluted compounds (1:100). For example,for 100 ul of STF293 cells, 100 ul of Wnt3a-conditioned media and 2 ulof drug will be added to each well. The final concentrations shouldtherefore be 100 μM, 30 μM, 10 μM, 3 μM, 1 μM, 300 nM, 100 nM, 30 nM, 10nM, 3 nM, 1 nM, and 0.3 nM. On the second day, the media is removed and75 ul of Passive Lysis Buffer (Promega) is added to each well. The platewill be shaken at 130 rpm for 15 minutes. For the Steady Glo assay, 45ul of the lysis is removed and added to a white 96-well plate containing45 uL/well of Steady Glo solution (Promega). For the Cell Titer assay,25 ul of the lysis is transferred to a white 96-well plate containing 25ul/well of Cell Titer solution (Promega). Both Steady Glo and Cell Titerassays will be read with a luminescence plate reader. When determiningEC₅₀, the Steady Glo values will be divided by the Cell Titer values tonormalize for cell number and the resulting values plotted in adose-response curve.

Example 64. Activity in Reporter Assays Experimental

All compounds were tested using the human cell line HEK STF293. Thiscell line carries a Wnt reporter (TCF/LEF 1 promoter), which drivesexpression of the firefly luciferase protein. The level of Wnt activityis directly correlated with the level of luciferase activity (determinedusing a simple assay). Compounds that inhibit Wnt signaling by reducingluciferase activity in these two cell lines are further testedbiochemically. Biochemical confirmation that compounds inhibit Wntsignaling is obtained by immunoblotting for beta-catenin in HEK STF293cells and demonstrating that its levels are reduced.

Compounds were prepared as 10 mM stocks for each compound in DMSO.Dilutions were prepared in a 96-well plate in DMSO. The stock dilutionsare as follows: 10 mM, 1 mM, 100 μM, 10 μM, 100 nM, and 10 nM. Plateswere sealed and stored at −20 C.

HEK STF293 cells were seeded at approximately 25,000-30,000 cells/wellin a 96-well (100 uL volume). On the first day, Wnt3a-conditioned media(1:1) were added along with diluted compounds (1:100). For example, for100 ul of STF293 cells, 100 ul of Wnt3a-conditioned media and 2 ul ofdrug was added to each well. The final concentrations should thereforebe 100 uM, 10 uM, 1 uM, 100 nM, 10 nM, and 1 nM. On the second day, themedia is removed and 75 ul of Passive Lysis Buffer (Promega) is added toeach well. The plate is shaken at 130 rpm for 15 minutes. For the SteadyGlo assay, 45 ul of the lysis is removed and added to a white 96-wellplate containing 45 uL/well of Steady Glo solution (Promega). For theCell Titer assay, 25 ul of the lysis is transferred to a white 96-wellplate containing 25 ul/well of Cell Titer solution (Promega). BothSteady Glo and Cell Titer assays were read with a luminescence platereader. When determining EC50, the Steady Glo values were divided by theCell Titer values to normalize for cell number.

The control CMV driven cell line assay was performed as recited abovefor the STF293 assay except that no Wnt3a-conditioned media was added tothe plated cells and 1 ul of diluted compound was added instead of 2 ul.

Three concentrations were chosen based on the EC50 curves from theSTF293 assay. From the original 10 mM stocks, the following dilutionswere prepared in DMSO and stored at −20 C: 100 uM, 50 uM, and 10 uM.

HEK293 cells were seeded in a 6-well plate at approximately 8.0×10⁵cells (2 mL per well). On the first day, Wnt3a-conditioned media (1:1)and compounds (1:100) were added to the plated cells. The finalconcentrations of compounds were luM, 500 nM, and 100 nM. Vehicle (DMSO)and a Wnt3a-conditioned media plus Vehicle samples were also prepared ascontrols. Lysates were collected (with non-denaturing lysis buffer)after 24 hours incubation, and protein concentrations determined byBradford Assay. Immunoblotting with an anti-beta-catenin antibody(equivalent amounts of protein/lane for each condition) weresubsequently performed to determine beta-catenin levels.

Results.

Included in Tables 1 and 2 below are compounds that showed inhibitoryactivity in the HEK STF293 assay disclosed above.

TABLE 1 Structure EC₅₀

++

+

++

+

+

+

+

+

+

++

+

+ ++ indicates an EC50 equal to or below 100 nM + indicates an EC50above 100 nM

TABLE 2 Compound Cmpd Name

N-(4-fluorophenyl)- 4-(indolin-1- ylsulfonyl) benzamide

N-(4-(N-p- tolylsulfamoyl)phenyl)- 4,5-dihydro-1H- benzo[g]indazole-3-carboxamide

N-(4-(N-(2,5- dimethylphenyl) sulfamoyl)phenyl)-4,5- dihydro-1H-benzo[g]indazole-3- carboxamide

N-(5,6- dimethoxybenzo[d] thiazol-2-yl)-4- (N-methyl- N-phenylsulfamoyl)benzamide

N-(5,6- dimethoxybenzo[d] thiazol-2-yl)-4- (indolin-1- ylsulfonyl)benzamide

4-(3,4- dihydroquinolin- 1(2H)-ylsulfonyl)-N- (4-(pyridin-2-yl)thiazol-2- yl)benzamide

4-(indolin-1- ylsulfonyl)-N-(5- methyl-4- phenylthiazol-2- yl)benzamide

N-(2- carbamoylphenyl)-3- (N- phenylsulfamoyl) benzamide

4-(3,4- dihydroquinolin- 1(2H)-ylsulfonyl)- N-(4-p-tolylthiazol-2-yl)benzamide

4-(3,4- dihydroquinolin- 1(2H)-ylsulfonyl)-N- (4-phenylthiazol-2-yl)benzamide

4-(3,4- dihydroquinolin- 1(2H)-ylsulfonyl)- N-(6- methylbenzo[d]thiazol-2- yl)benzamide

N-(4-(4- acetamidophenyl) thiazol-2-yl)-4-(3,4- dihydroquinolin- 1(2H)-ylsulfonyl)benzamide

3-(3,4- dihydroquinolin- 1(2H)-ylsulfonyl)- N-(4-(pyridin-2-yl)thiazol-2- yl)benzamide

3-(indolin-1- ylsulfonyl)-N-(4- (pyridin-2-yl)thiazol-2- yl)benzamide

4-(3,4- dihydroquinolin- 1(2H)-ylsulfonyl)- N-(3- methoxyphenyl)benzamide

4-(3,4- dihydroquinolin- 1(2H)-ylsulfonyl)-N- (3-(1-hydroxyethyl)phenyl) benzamide

4-(3,4- dihydroquinolin- 1(2H)-ylsulfonyl)- N-(pyridin-4- yl)benzamide

4-(N-(4-fluorophenyl)- N-methylsulfamoyl)- N-(4-(pyridin-2-yl)thiazol-2- yl)benzamide

4-(N-(4- chlorophenyl)-N- methylsulfamoyl)- N-(4-(pyridin-2-yl)thiazol-2- yl)benzamide

4-(N-methyl-N-(4- (trifluoromethyl) phenyl)sulfamoyl)- N-(4-(pyridin-2-yl)thiazol-2- yl)benzamide

4-(N-(4- methoxyphenyl)-N- methylsulfamoyl)- N-(4-(pyridin-2-yl)thiazol-2- yl)benzamide

4-(5-chloroindolin-1- ylsulfonyl)-N-(4- (pyridin-2-yl)thiazol-2-yl)benzamide

4-(5-chloroindolin- 1-ylsulfonyl)-N-(6- methoxybenzo[d] thiazol-2-yl)benzamide

4-(3,4- dihydroquinolin- 1(2H)-ylsulfonyl)-2- fluoro-N-(4-(pyridin-2-yl)thiazol-2- yl)benzamide

4-(3,4- dihydroquinolin- 1(2H)-ylsulfonyl)- N-(3-(4- fluorophenyl)-1H-pyrazol-5- yl)benzamide

4-(N-(4- methoxyphenyl) sulfamoyl)-N- (4-(pyridin-2- yl)thiazol-2-yl)benzamide

4-(N-(3- chlorophenyl) sulfamoyl)-N-(4- (pyridin-2- yl)thiazol-2-yl)benzamide

4-(N-(3- methoxyphenyl)-N- methylsulfamoyl)- N-(4-(pyridin-2-yl)thiazol-2- yl)benzamide

4-(N-(2- methoxyphenyl)-N- methylsulfamoyl)- N-(4-(pyridin-2-yl)thiazol-2- yl)benzamide

N-(4-(pyridin-2- yl)thiazol-2-yl)-4-(N- m- tolylsulfamoyl) benzamide

4-(N-(4- methoxyphenyl)-N- methylsulfamoyl)- N-(6- methylbenzo[d]thiazol-2- yl)benzamide

N-(6- methoxybenzo[d] thiazol-2-yl)-4-(N-(4- methoxyphenyl)-N-methylsulfamoyl) benzamide

N-(4-(4- acetamidophenyl) thiazol-2-yl)-4-(N-(4- methoxyphenyl)-N-methylsulfamoyl) benzamide

4-(N-(4- methoxyphenyl)-N- methylsulfamoyl)-N- (pyridin-4- yl)benzamide

N-(3-(1- hydroxyethyl) phenyl)-4-(N-(4- methoxyphenyl)-N-methylsulfamoyl) benzamide

N-(4-(4- acetamidophenyl) thiazol-2-yl)-3-(indolin-1-ylsulfonyl)benzamide

N-(3-(4- fluorophenyl)-1H- pyrazol-5-yl)-3- (indolin-1- ylsulfonyl)benzamide

4-(N-(4- (benzyloxy)phenyl)-N- methylsulfamoyl)-N- (4-(pyridin-2-yl)thiazol-2- yl)benzamide

Example 65. Functional (Cell Proliferation) Assay Experimental

Viability of colorectal (CRC) cells (SW480 cells, DLD-1 cells, HCT 116cells, and SW620 cells) in the presence of compounds was performed usingthe CellTiter-Glo) assay (Promega) according to manufacturer'sinstructions. This luminescence-based assay is sensitive (can measuredown to 15 cells/well) and allows for multi-well formats. The assaymeasures the amount of ATP, which is proportional to the number of cellspresent in the culture. Briefly, cells are plated onto 96-well plates atlow density in the presence of normal growth media and increasingconcentration of compounds. The number of viable cells is thendetermined 48 and 72 hours later and compared with the vehicle treatedcontrols.

Results.

Certain compounds of the present invention showed anti-proliferationactivity.

What is claimed is:
 1. A process for preparing a compound of Formula(VIIIA), the process comprising: contacting a compound of formula (aa):

with a compound of formula (bb):

to form the compound of Formula (VIIIA):

wherein: X¹ and X² are independently carbon or nitrogen; L¹ is NH—C(O)—;R² is hydrogen, halogen, —CN, —CF₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —CN, —CF₃, —NR^(5A)—C(O)R^(5B),—NR^(5A)—C(O)—OR^(5B), —C(O)NR^(5A)R^(5B), —NR^(5A)S(O)₂R^(5B),—S(O)₂N(R^(5A))(R^(5B)), —SR^(5A), —S(O)R^(5B), —S(O)₂R^(5B),—NR^(5A)R^(5B), —OR^(5A), —C(O)R^(5B), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; wherein R² is optionally joined together with R⁵ to form asubstituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl; R⁶ is independently halogen, —CN, —CF₃,—NR^(6A)—C(O)R^(6B), —NR^(6A)—C(O)—OR^(6B), —C(O)NR^(6A)R^(6B),—NR^(6A)S(O)₂R^(6B), —S(O)₂N(R^(6A))(R^(6B)), —SR^(6A), — S(O)R^(6B),—S(O)₂R^(6B), —NR^(6A)R^(6B), —OR^(6A), —C(O)R^(6B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁸ is hydrogen, halogen, CN,—NR^(8A)—C(O)R^(8B), —NR^(8A)—C(O)—OR^(8B), —C(O)NR^(8A)R^(8B),—NR^(8A)S(O)₂R^(8B), —S(O)₂N(R^(8A))(R^(8B)), —SR^(8A), —S(O)R^(8B),—S(O)₂R^(8B), —NR^(8A)R^(8B), —OR^(8A), —C(O)R^(8B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁹ is independently halogen, —CN, —CF₃,—NR^(9A)—C(O)R^(9B), —NR^(9A)—C(O)—OR^(9B), —C(O)NR^(9A)R^(9B),—NR^(9A)S(O)₂R^(9B), —S(O)₂N(R^(9A))(R^(9B)), —SR^(9A), —S(O)R^(9B),—S(O)₂R^(9B), —NR^(9A)R^(9B), —OR^(9A), —C(O)R^(9B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(5A), R^(5B), R^(6A), R^(6B), R^(8A) andR^(8B) are independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(9A)and R^(9B) are independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; u isan integer from 0 to 5; and z is an integer from 0 to
 4. 2. The processof claim 1, wherein the process is carried out in the presence ofhydroxybenzotriazole (HOBt),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) andN,N-diisopropylethylamine (DIEPA) in dimethylformamide (DMF).
 3. Theprocess of claim 2, wherein the ratio of HOBt, EDC and DIEPA is1.5:1.5:2.5.
 4. The process of claim 1, wherein the process is carriedout in the presence of DIPEA andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(pybop) in DMF.
 5. The process of claim 4, wherein the ratio of DIPEAand pybop is 3:1.5.
 6. The process of claim 4, wherein the process iscarried out at about 40° C.
 7. The process of claim 1, wherein theprocess is carried out at room temperature.
 8. The process of claim 1,wherein the ratio of the compound of formula (aa) and compound offormula (bb) is 1.2 to
 1. 9. The process of claim 1, wherein compound(aa) is prepared by contacting a compound of the formula (cc):

with a compound of formula (dd):


10. The process of claim 9, wherein the process is commenced in methanolat a temperature of 0° C., then continued at room temperature.
 11. Theprocess of claim 9, wherein the ratio of the compound of formula (cc)and compound of formula (dd) is 1 to
 3. 12. The process of claim 1,wherein z is an integer from 1 to
 4. 13. The process of any of claim 1,wherein R⁵ is halogen, —CN, —CF₃, —NR^(5A)—C(O)R^(5B),—NR^(5A)—C(O)—OR^(5B), —C(O)NR^(5A)R^(5B), —NR^(5A)S(O)₂R^(5B),—S(O)₂N(R^(5A))(R^(5B)), —SR^(5A), —S(O)R^(5B), —S(O)₂R^(5B),—NR^(5A)R^(5B), —OR^(5A), —C(O)R^(5B), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; wherein R² is optionally joined together with R⁵ to form asubstituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl; or wherein R⁵ is hydrogen, halogen, —CN, —CF₃,—NR^(5A)—C(O)R^(5B), —NR^(5A)—C(O)—OR^(5B), —C(O)NR^(5A)R^(5B),—NR^(5A)S(O)₂R^(5B), —S(O)₂N(R^(5A))(R^(5B)), —SR^(5A), —S(O)R^(5B),—NR^(5A)R^(5B), —C(O)R^(5B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;wherein R² is optionally joined together with R⁵ to form a substitutedor unsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl; or wherein R² and R⁵ are not joined together to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl.
 14. The process of claim 1, wherein R⁶ isindependently halogen, —CN, —CF₃, —NR^(6A)—C(O)R^(6B),—NR^(6A)—C(O)—OR^(6B), —C(O)NR^(6A)R^(6B), —NR^(6A)S(O)₂R^(6B),—S(O)₂N(R^(6A))(R^(6B)), —SR^(6A), —S(O)R^(6B), —S(O)₂R^(6B),—NR^(6A)R^(6B), —C(O)R^(6B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. 15.The process of claim 1, wherein the compound of Formula (VIIIA) has theformula: